# Patent

## Title
Azepino[4,5-B]indoles and methods of use

## Abstract

This disclosure relates to new azepino[4,5-b]indole compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new 1,2,3,4,5,6-tetrahydroazepino[4,5-b]indoles. Pharmaceutical compositions are also provided.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. Non-provisional patent application Ser. No. 12/610,152, filed on Oct. 30, 2009, which claims priority to U.S. Provisional Patent Application No. 61/110,527 filed Oct. 31, 2008, U.S. Provisional Patent Application No. 61/173,965 filed Apr. 29, 2009 and U.S. Provisional Patent Application No. 61/245,257 filed Sep. 23, 2009, the disclosures of each of which are hereby incorporated herein by reference in their entireties.


STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
Not applicable.
BACKGROUND OF THE INVENTION
Neurotransmitters such as histamine, serotonin, dopamine and norepinephrine mediate a large number of processes in the central nervous system (CNS) as well as outside the CNS. Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited to, Alzheimer's disease, Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia (such as cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia), anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression, attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD) and a variety of allergic diseases. Compounds that modulate these neurotransmitters may be useful therapeutics.
Histamine receptors belong to the superfamily of G protein-coupled seven transmembrane proteins. G protein-coupled receptors constitute one of the major signal transduction systems in eukaryotic cells. Coding sequences for these receptors, in those regions believed to contribute to the agonist-antagonist binding site, are strongly conserved across mammalian species. Histamine receptors are found in most peripheral tissue and within the central nervous system. Compounds capable of modulating a histamine receptor may find use in therapy, e.g., histamine antagonists may find use as antihistamines.
Dimebon is a known anti-histamine drug that has also been characterized as a neuroprotective agent useful to treat, inter alia, neurodegenerative diseases. Dimebon has been shown to inhibit the death of brain cells (neurons) in preclinical models of Alzheimer's disease and Huntington's disease, making it a novel potential treatment for these and other neurodegenerative diseases. In addition, dimebon has been shown to improve the mitochondrial function of cells in the setting of cellular stress with very high potency. For example, dimebon treatment improved mitochondrial function and increased the number of surviving cells after treatment with the cell toxin ionomycin in a dose dependent fashion. Dimebon has also been shown to promote neurite outgrowth and neurogenesis, processes important in the formation of new and/or enhanced neuronal cell connections, and evidence of dimebon's potential for use in additional diseases or conditions. See, e.g., U.S. Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos. PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077, PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645, PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626, PCT/US2008/009357, PCT/US2007/024623, PCT/US2008/008121, and PCT/US2009/032065. Hydrogenated pyrido[4,3-b]indoles and uses thereof have been disclosed in PCT Patent Application Nos. PCT/US2008/081390, PCT/US2009/032065 and PCT/US2009/038142. Hydrogenated pyrido[3,4-b]indoles and uses thereof have been described in PCT/US2009/038138. All references disclosed herein and throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.
Although dimebon holds great promise as a drug for the treatment of neurodegenerative diseases and/or diseases in which neurite outgrowth and/or neurogenesis may be implicated in therapy, there remains a need for new and alternative therapies for the treatment of such diseases or conditions. In addition, there remains a need for new and alternative antihistamine drugs, preferably ones in which side-effects such as drowsiness are reduced or eliminated. Compounds that exhibit enhanced and/or more desirable properties than dimebon (e.g., superior safety and efficacy) may find particular use in the treatment of at least those indications for which dimebon is believed to be advantageous. Further, compounds that exhibit a different therapeutic profile than dimebon as determined, e.g. by in vitro and/or in vivo assays, may find use in additional diseases and conditions.
BRIEF SUMMARY OF THE INVENTION
Azepino[4,5-b]indole compounds of the general Formula (I) are described as new histamine receptor modulators. Other compounds are also detailed herein. Compositions comprising the compounds are provided, as are kits comprising the compound as well as methods of using and making the compounds. Compounds of the invention may also find use in treating neurodegenerative diseases. Compounds of the invention may also find use in treating diseases and/or conditions in which modulation of aminergic G protein-coupled receptors and/or neurite outgrowth may be implicated in therapy. Compounds disclosed herein may find use in the methods disclosed herein, including use in treating, preventing, delaying the onset and/or delaying the development of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder in an individual in need thereof, such as humans.
The invention embraces compounds of the formula (I):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each of m and q is independently 0 or 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
provided that the compound is other than a compound in Table 1;
or a salt or solvate thereof.
In one variation, the compounds of the invention, pharmaceutical compositions thereof, isolated forms thereof and methods of using and administering the compounds detailed herein, encompass any of the compounds of Formula (I), including those listed in Table 1 or a salt thereof.








TABLE 1





Compound



No.
Compound Structure







 1x
1-Propanone, 3-(diethylamino)-1-[1,4,5,6-tetrahydro-6-(phenylmethyl)azepino[4,5-



b]indol-3(2H)-yl]-


 2x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-3,5,6-tris(phenylmethyl)-


 3x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-3,6-bis(phenylmethyl)-


 4x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5-(2-oxo-2-phenylethyl)-3,6-



bis(phenylmethyl)-


 5x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5-(2-oxo-2-phenylethyl)-6-



(phenylmethyl)-


 6x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5,5-diphenyl-3,6-



bis(phenylmethyl)-


 7x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5,5-diphenyl-6-(phenylmethyl)-


 8x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5,6-bis(phenylmethyl)-


 9x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5-phenyl-3,6-bis(phenylmethyl)-


 10x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5-phenyl-6-(phenylmethyl)-


 11x
Azepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-6-(phenylmethyl)-


 12x
Azepino[4,5-b]indol-5(2H)-one, 1,3,4,6-tetrahydro-3-methyl-6-(phenylmethyl)-


 13x
Azepino[4,5-b]indol-5-ol, 1,2,3,4,5,6-hexahydro-6-(m-methoxybenzyl)-3-methyl-


 14x
Azepino[4,5-b]indol-5-ol, 1,2,3,4,5,6-hexahydro-8-methoxy-6-(m-methoxybenzyl)-



3-methyl-


 15x
Azepino[4,5-b]indol-5-ol, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-


 16x
Azepino[4,5-b]indol-5-ol, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-, acetate (ester)


 17x
Azepino[4,5-b]indol-5-ol, 6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-


 18x
Azepino[4,5-b]indol-5-ol, 6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-


 19x
Azepino[4,5-b]indol-5-ol, 6-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-


 20x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3,5,6-tris(phenylmethyl)-


 21x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3,6-bis(phenylmethyl)-


 22x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3-methyl-6-(2-pyridylmethyl)-


 23x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3-methyl-6-(alpha-methylbenzyl)-


 24x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3-methyl-6-[3-(4-methyl-1-



piperazinyl)propyl]-


 25x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5,5-diphenyl-3,6-bis(phenylmethyl)-


 26x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5,5-diphenyl-6-(phenylmethyl)-


 27x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5,6-bis(phenylmethyl)-


 28x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5-phenyl-3,6-bis(phenylmethyl)-


 29x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5-phenyl-6-(phenylmethyl)-


 30x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-


 31x
Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-6-[(3-methoxyphenyl)methyl]-3-



methyl-


 32x
Azepino[4,5-b]indole, 10-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-


 33x
Azepino[4,5-b]indole, 10-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-


 34x
Azepino[4,5-b]indole, 3-(1H-benzimidazol-2-ylmethyl)-1,2,3,4,5,6-hexahydro-5-



phenyl-6-(phenylmethyl)-


 35x
Azepino[4,5-b]indole, 3-(3-chloro-1-oxopropyl)-1,2,3,4,5,6-hexahydro-6-



(phenylmethyl)- (9CI)


 36x
Azepino[4,5-b]indole, 3-(chloroacetyl)-1,2,3,4,5,6-hexahydro-5-phenyl-6-



(phenylmethyl)-


 37x
Azepino[4,5-b]indole, 3-ethyl-1,2,3,4,5,6-hexahydro-10-methyl-6-(phenylmethyl)-


 38x
Azepino[4,5-b]indole, 3-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-(phenylmethyl)-


 39x
Azepino[4,5-b]indole, 3-ethyl-1,2,3,4,5,6-hexahydro-8-methyl-6-(phenylmethyl)-


 40x
Azepino[4,5-b]indole, 3-ethyl-1,2,3,4,5,6-hexahydro-9-methyl-6-(phenylmethyl)


 41x
Azepino[4,5-b]indole, 6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,2,3,4,5,6-



hexahydro-


 42x
Azepino[4,5-b]indole, 6-[(2-chlorophenyl)methyl]-1,2,3,4,5,6-hexahydro-3-methyl-


 43x
Azepino[4,5-b]indole, 6-[(4-chlorophenyl)methyl]-3-ethyl-1,2,3,4,5,6-hexahydro-


 44x
Azepino[4,5-b]indole, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-


 45x
Azepino[4,5-b]indole, 6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-


 46x
Azepino[4,5-b]indole, 8,9-dichloro-1,2,3,4,5,6-hexahydro-6-(3-phenylpropyl)-


 47x
Azepino[4,5-b]indole, 8-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-


 48x
Azepino[4,5-b]indole, 8-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-


 49x
Azepino[4,5-b]indole, 9,10-dichloro-1,2,3,4,5,6-hexahydro-6-(3-phenylpropyl)-


 50x
Azepino[4,5-b]indole, 9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-


 51x
Azepino[4,5-b]indole, 9-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-


 52x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-



(phenylamino)ethyl]-, 1,1-dimethylethyl ester


 53x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-[(3-



methylphenyl)amino]-2-oxoethyl-, 1,1-dimethylethyl ester


 54x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-[(4-



methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester


 55x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-



[[(phenylamino)carbonyl]amino]ethyl]-, 1,1-dimethylethyl ester


 56x
Azepino[4,5-b]indole-3(2H)-carboxylic acid,1,4,5,6-tetrahydro-6-[2-oxo-2-



(phenylamino)ethyl]-, 1,1-dimethylethyl ester


 57x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-oxo-2-[(2,4,6-



trimethylphenyl)amino]ethyl]-, 1,1-dimethylethyl ester


 58x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[3-[(4-



methoxyphenyl)amino]-3-oxopropyl]-, 1,1-dimethylethyl ester


 59x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 10-bromo-1,4,5,6-tetrahydro-6-[2-[(4-



methyl-2-thiazolyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester


 60x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-(1H-benzimidazol-2-ylmethyl)-10-



bromo-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 61x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-(2-amino-2-oxoethyl)-1,4,5,6-



tetrahydro-, 1,1-dimethylethyl ester


 62x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-(2-aminoethyl)-1,4,5,6-tetrahydro-,



1,1-dimethylethyl ester


 65x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-[2-(benzoylamino)ethyl]-1,4,5,6-



tetrahydro-, 1,1-dimethylethyl ester


 66x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-[2-(dimethylamino)-2-oxoethyl]-



1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 67x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-[2-[(2,3-dimethylphenyl)amino]-2-



oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 68x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 6-[2-[(2-fluoro-4-



methylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 69x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 7-bromo-1,4,5,6-tetrahydro-6-[2-[(4-



methyl-2-thiazolyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester


 70x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 8,9-dichloro-1,4,5,6-tetrahydro-6-(3-



phenylpropyl)-, 1,1-dimethylethyl ester


 71x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 8,9-dichloro-1,4,5,6-tetrahydro-6-[2-



[(4-methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester


 72x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 8,9-dichloro-1,4,5,6-tetrahydro-6-[2-



oxo-2-(phenylamino)ethyl]-, 1,1-dimethylethyl ester


 73x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 8,9-dichloro-6-[2-[(2,3-



dimethylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 74x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 9,10-dichloro-1,4,5,6-tetrahydro-6-(3-



phenylpropyl)-, 1,1-dimethylethyl ester


 75x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 9,10-dichloro-1,4,5,6-tetrahydro-6-[2-



[(4-methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester


 76x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 9,10-dichloro-1,4,5,6-tetrahydro-6-[2-



oxo-2-(phenylamino)ethyl]-,1,1-dimethylethyl ester


 77x
Azepino[4,5-b]indole-3(2H)-carboxylic acid, 9,10-dichloro-6-[2-[(2,3-



dimethylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester


 78x
Azepino[4,5-b]indole-3,6-dicarboxylic acid, 5-[3,3-dimethoxy-2-



(methoxycarbonyl)propyl]-1,2,4,5-tetrahydro-, 3,6-bis(1,1-dimethylethyl) ester


 80x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-


 81x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N,N-dimethyl-


 82x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-2-pyridinyl-


 83x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-3-pyridinyl-


 84x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-phenyl-


 85x
Azepino[4,5-b]indole-6(1H)-acetamide, 10-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2-



thiazolyl)-


 86x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(2,4,6-



trimethylphenyl)-


 87x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(3-methoxyphenyl)-


 88x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(3-methylphenyl)-


 89x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(3-nitrophenyl)-


 90x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(4-methoxyphenyl)-


 91x
Azepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(4-methyl-2-thiazolyl)-


 92x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(5,6,7,8-tetrahydro-1-



naphthalenyl)-


 93x
Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-[2-methyl-3-



(trifluoromethyl)phenyl]-


 94x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


 95x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


 96x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


 97x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


 98x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


 99x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


100x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


101x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


102x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


103x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


104x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


105x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


106x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


107x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


108x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


109x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


110x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


111x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


112x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


113x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


114x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


115x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


116x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


117x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


118x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


119x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


120x
Azepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


121x
Azepino[4,5-b]indole-6(1H)-acetamide, 7-bromo-2,3,4,5-tetrahydro-N-(4-



methoxyphenyl)-


122x
Azepino[4,5-b]indole-6(1H)-acetamide, 7-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2-



thiazolyl)-


123x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


124x
Azepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


125x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


126x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


127x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


128x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


129x
Azepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


130x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


131x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,10-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


132x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-(4-



methoxyphenyl)-


133x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


134x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


135x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


136x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


137x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


138x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-2,3,4,5-tetrahydro-N-phenyl-


139x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


140x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


141x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


142x
Azepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


143x
Azepino[4,5-b]indole-6(1H)-acetamide, 8-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2-



thiazolyl)-


144x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-(4-



methoxyphenyl)-


145x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-(4-



methyl-2-thiazolyl)-


146x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-(4-



phenyl-2-thiazolyl)-


147x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8-



tetrahydro-1-naphthalenyl)-


148x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-(5-



methyl-2-thiazolyl)-


149x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1-



methylethyl)phenyl]-


150x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-2,3,4,5-tetrahydro-N-phenyl-


151x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-N-(2,3-dimethylphenyl)-



2,3,4,5-tetrahydro-


152x
Azepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-N-(3-ethylphenyl)-2,3,4,5-



tetrahydro-


153x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-N-[3-(1,1-



dimethylethyl)phenyl]-2,3,4,5-tetrahydro-


154x
Azepino[4,5-b]indole-6(1H)-acetamide, 9,10-dichloro-N-[4-(1,1-dimethylethyl)-2-



thiazolyl]-2,3,4,5-tetrahydro-


155x
Azepino[4,5-b]indole-6(1H)-acetamide, 9-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2-



thiazolyl)-


156x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(1,3-dihydro-4-isobenzofuranyl)-2,3,4,5-



tetrahydro-


157x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(2,3-dimethylphenyl)-2,3,4,5-tetrahydro-


158x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(2,4-dimethoxyphenyl)-2,3,4,5-



tetrahydro-


159x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(2-fluoro-4-methylphenyl)-2,3,4,5-



tetrahydro-


160x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(3,5-dimethoxyphenyl)-2,3,4,5-



tetrahydro-


161x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(3-chloro-2-methylphenyl)-2,3,4,5-



tetrahydro-


162x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(3-chloro-4-fluorophenyl)-2,3,4,5-



tetrahydro-


163x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(4-cyanophenyl)-2,3,4,5-tetrahydro-


164x
Azepino[4,5-b]indole-6(1H)-acetamide, N-(4-fluorophenyl)-2,3,4,5-tetrahydro-


165x
Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-7,10-dichloro-2,3,4,5-



tetrahydro-


166x
Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-7,8-dichloro-2,3,4,5-



tetrahydro-


167x
Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-7,9-dichloro-2,3,4,5-



tetrahydro-


168x
Azepino [4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-8,10-dichloro-2,3,4,5-



tetrahydro-


169x
Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-8,9-dichloro-2,3,4,5-



tetrahydro-


170x
Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-9,10-dichloro-2,3,4,5-



tetrahydro-


171x
Azepino[4,5-b]indole-6(1H)-acetic acid, 10-bromo-2,3,4,5-tetrahydro-, 2-



methylpropyl ester


172x
Azepino[4,5-b]indole-6(1H)-acetic acid, 9,10-dichloro-2,3,4,5-tetrahydro-, ethyl



ester


173x
Azepino[4,5-b]indole-6(1H)-ethanamine, 2,3,4,5-tetrahydro-


174x
Azepino[4,5-b]indole-6(1H)-ethanamine, 2,3,4,5-tetrahydro-N-phenyl-


176x
Azepino[4,5-b]indole-6(1H)-propanamide, 2,3,4,5-tetrahydro-N-(4-methoxyphenyl)-


177x
Azepino[4,5-b]indole-6(1H)-propanamine, 2,3,4,5-tetrahydro-N,N,3,9-tetramethyl-


178x
Azepino[4,5-b]indole-6(1H)-propanamine, 2,3,4,5-tetrahydro-N,N,3-trimethyl-


179x
Azepino[4,5-b]indole-6(1H)-propanoic acid, 3-benzoyl-2,3,4,5-tetrahydro-, ethyl



ester


180x
Azepino[4,5-b]indole-6-acetic acid, 10-bromo-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


181x
Azepino[4,5-b]indole-6-acetic acid, 10-bromo-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, 2-methylpropyl ester


182x
Azepino[4,5-b]indole-6-acetic acid, 3-[(1,1-dimethylethoxy)carbonyl]-1,2,4,5-



tetrahydro-, ethyl ester


183x
Azepino[4,5-b]indole-6-acetic acid, 3-[(1,1-dimethylethoxy)carbonyl]-1,2,4,5-



tetrahydro-7-nitro-, ethyl ester


184x
Azepino[4,5-b]indole-6-acetic acid, 7,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


185x
Azepino[4,5-b]indole-6-acetic acid, 7,8-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


186x
Azepino[4,5-b]indole-6-acetic acid, 7,9-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


187x
Azepino[4,5-b]indole-6-acetic acid, 8,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


188x
Azepino[4,5-b]indole-6-acetic acid, 8,9-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


189x
Azepino[4,5-b]indole-6-acetic acid, 9,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]-



1,2,4,5-tetrahydro-, ethyl ester


190x
Azepino[4,5-b]indole-9-carboxylic acid, 1,2,3,4,5,6-hexahydro-3-methyl-6-



(phenylmethyl)-, ethyl ester


191x
Benzamide, N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]-


192x
Ethanone, 2-(diethylamino)-1-[1,4,5,6-tetrahydro-5-phenyl-6-



(phenylmethyl)azepino[4,5-b]indol-3(2H)-yl]-


193x
Ethanone, 2-[1,2,3,4,5,6-hexahydro-3,6-bis(phenylmethyl)azepino[4,5-b]indol-5-yl]-



1-phenyl-


194x
Ethanone, 2-[1,2,3,4,5,6-hexahydro-6-(phenylmethyl)azepino[4,5-b]indol-5-yl]-1-



phenyl-









The invention also embraces compounds of the formula (I) wherein each of m and q is 0 (Formula (Ia)). In another variation, the compound is of the formula (I) wherein each of m and q is 1 (Formula (Ib)). In another variation, the compound is of the formula (I) wherein m=1 and q=0 (Formula (Ic)). In one embodiment, the compound is of the formula (I) wherein m=1, q=0 and R8c and R8e are taken together to form a bond (Formula (C)).
In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where Q is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or a unsubstituted heterocyclyl, or a salt or solvate thereof. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where Q is a heterocycle, such as a 5, 6 or 7 membered carbocycle.
In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where Q is substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, or a salt or solvate thereof. In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where Q is substituted or unsubstituted heteroaryl, such as a 5, 6 or 7 membered heteroaryl. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where Q is a substituted or unsubstituted aryl, such as a 5, 6 or 7 membered aryl, or a salt or solvate thereof.
The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers, including geometric isomers, of a compound depicted. Unless olefin geometry is explicitly indicated, substituted olefinic bonds may be present as cis or trans or (Z) or (E) isomeric forms, or as mixtures thereof. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. For example, where only a Z form of a compound is specifically listed, it is understood that the E form of the compound is also embraced. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
The invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Kits comprising a compound of the invention and instructions for use are also embraced by this invention. Compounds as detailed herein or a pharmaceutically acceptable salt thereof are also provided for the manufacture of a medicament for the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.
The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
In one aspect, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of any one or more of the following: cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders in individuals in need thereof, such as humans. In one variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of diseases or conditions for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial. In one variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of any one or more of diseases or conditions for which neurite outgrowth and/or neurogenesis and/or neurotrophic effects are believed to be or are beneficial. In another variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of diseases or conditions for which the modulation of an aminergic G protein-coupled receptor and neurite outgrowth and/or neurogenesis and/or neurotrophic effects are believed to be or are beneficial. In one variation, the disease or condition is a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
In another aspect, compounds of the invention are used to improve cognitive function and/or reduce psychotic effects in an individual, comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to improve cognitive function and/or reduce psychotic effects.
In a further aspect, compounds of the invention are used to stimulate neurite outgrowth and/or promote neurogenesis and/or enhance neurotrophic effects in an individual comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and/or to promote neurogenesis and/or to enhance neurotrophic effects. Synapse loss is associated with a variety of neurodegenerative diseases and conditions including Alzheimer's disease, schizophrenia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, head trauma and spinal cord injury. Compounds of the invention that stimulate neurite outgrowth may have a benefit in these settings.
In another aspect, compounds described herein are used to modulate an aminergic G protein-coupled receptor comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to modulate an aminergic G protein-coupled receptor. In one variation, a compound of the invention modulates at least one of the following receptors: adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histamine receptor (e.g., H1, H2 and/or H3). In another variation, at least two of the following receptors are modulated: adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histamine receptor (e.g., H1, H2 and/or H3). In another variation, at least three of the following receptors are modulated: adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histamine receptor (e.g., H1, H2 and/or H3). In another variation, each of the following receptors is modulated: adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histamine receptor (e.g., H1, H2 and/or H3). In another variation, at least one of the following receptors is modulated: a1D, a2A, a2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2, H1, H2 and H3. In another variation, at least one of the following receptors is modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, H1, H2 and H3. In another variation, at least two or three or four or five or six or seven or eight or nine or ten or eleven of the following receptors are modulated: a1D, a2A, a2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2, H1, H2 and H3. In another variation, at least two or three or four or five or six or seven or eight or nine or ten or eleven of the following receptors are modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, H1, H2 and H3. In still another variation, at least dopamine receptor D2L is modulated. In another particular variation, at least dopamine receptor D2 and serotonin receptor 5-HT2A are modulated. In a particular variation, at least dopamine receptor D2L is modulated. In another particular variation, at least dopamine receptor D2L and serotonin receptor 5-HT2A are modulated. In a further particular variation, at least adrenergic receptors α1D, α2A, α2B and serotonin receptor 5-HT6 are modulated. In another particular variation, at least adrenergic receptors α1D, α2A, α2B, serotonin receptor 5-HT6 and one or more of serotonin receptor 5-HT7, 5-HT2A, 5-HT2C and histamine receptor H1 and H2 are modulated. In a further particular variation, histamine receptor H1 is modulated. In another variation, compounds of the invention exhibit any receptor modulation activity detailed herein and further stimulate neurite outgrowth and/or neurogenesis and/or enhance neurotrophic effects. In one variation, compounds detailed herein inhibit binding of a ligand to histamine receptor H1 and/or H2 by less than about 80% as determined by a suitable assay known in the art such as the assays described herein. In another variation, binding of a ligand to histamine receptor H1 and/or H2 is inhibited by less than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined by a suitable assay known in the art such as the assays described herein. In a further variation, compounds detailed herein: (a) inhibit binding of a ligand to histamine receptor H1 and/or H2 by less than about 80% (which can in different variations be less than about any of 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assay known in the art such as the assays described herein and (b) inhibit binding of a ligand to dopamine receptor D2L by greater than about any of 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% or between about 90% and about 100%, as determined in a suitable assay known in the art such as the assays described herein. In a further variation, compounds detailed herein: (a) inhibit binding of a ligand to histamine receptor H1 and/or H2 by less than about 80% (which can in different variations be less than about any of 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assay known in the art such as the assays described herein and (b) inhibit binding of a ligand to a dopamine receptor D2 by greater than about any of 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% or between about 90% and about 100%, as determined in a suitable assay known in the art such as the assays described herein.
The invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Kits comprising a compound of the invention and instructions for use are also embraced by this invention.
Compounds of the formula (I) are provided:




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof. In one aspect, compounds are of the formula (I) where, if applicable, any one or more of the following apply: X7, X8, X9 and X10 are CR4; at least one of X7, X8, X9 and X10 is N; at least two of X7, X8, X9 and X10 are N; two of X7, X8, X9 and X10 are N and two of X7, X8, X9 and X10 are CR4; one of X7, X8, X9 and X10 is N and three of X7, X8, X9 and X10 are CR4; if present, each R4 is independently H, halo, substituted or unsubstituted C1-C8 alkyl, C1-C8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl; if present, each R4 is independently H or a substituted or unsubstituted C1-C8 alkyl; if present, each R4 is H; if present, each R4 is independently H, halo, unsubstituted C1-C4 alkyl, C1-C4 perhaloalkyl or a substituted or unsubstituted aryl; if present, each R4 is independently H, halo, methyl, trifluoromethyl or cyclopropyl; X7, X8, X9 and X10 are taken together to provide an aromatic moiety selected from the group consisting of:




wherein each R4 is independently hydroxyl, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl; X7, X8, X9 and X10 are taken together provide an aromatic moiety selected from the group consisting of:





wherein R4 is hydroxyl, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl; if present, each R4 is independently halo, unsubstituted C1-C4 alkyl or C1-C4 perhaloalkyl; R1 is H, substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl; R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; R1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or R2a and R2b are taken together to form a carbonyl moiety; and each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano or nitro; each R2a and R2b is independently H, unsubstituted C1-C8 alkyl, halo or R2a and R2b are taken together to form a carbonyl moiety; each R3a and R3b is independently H, unsubstituted C1-C8 alkyl, halo or R3a and R3b are taken together to form a carbonyl moiety; each R2a and R2b is independently H, methyl, halo or R2a and R2b are taken together to form a carbonyl moiety; each R3a and R3b is independently H, methyl, halo or R3a and R3b are taken together to form a carbonyl moiety; each of R2a, R2b, R3a and R3b is H; n at least one of R2a, R2b, R3a and R3b is a substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; at least two of R2a, R2b, R3a and R3b is a substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; at least one of R2a, R2b, R3a and R3b is fluoro, methyl or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; either R2a and R2b or R3a and R3b are each methyl, fluoro or are taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R10a, R10b, R11a and R11b is independently H, halo, an unsubstituted C1-C8 alkyl, hydroxyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; each R10a, R10b, R11a and R11b is independently H, halo, an unsubstituted C1-C4 alkyl, hydroxyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; each R10a, R10b, R11a and R11b is independently H, bromo, methyl, hydroxyl or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; at least one of R10, R10b, R11a and R11b is an unsubstituted C1-C8 alkyl, hydroxyl, halo or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; at least one of R10, R10b, R11a and R11b is methyl, bromo, hydroxyl or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; both R10a and R10b are methyl or both R11a and R11b are methyl; R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl; R10a is H and R10b is methyl or bromo; the carbon bearing R10a and R10b is in the R configuration or the S configuration; R11a is H and R11b is methyl; the carbon bearing R11a and R11b is in the R configuration or the S configuration; R1, R2a, R2b, R3a, R3b, R10a, R11a and R11b are taken together to form a ring selected from the group consisting of:





each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, unsubstituted C1-C4 alkyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety; each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, methyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cyclopropyl moiety; at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a geminal R8 to form a methylene or a substituted methylene; at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 to form a bond; q is 0 and m is 1; q and m are both 0; q, m, R8a, R8b, R8c, R8d, R8e and R8f are taken together to form a moiety selected from the group consisting of:





R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; each R2a and R2b is independently H, methyl, fluoro or R2a and R2b are taken together to form a carbonyl moiety; each R3a and R3b is independently H or fluoro; each R10a and R10b is independently H, fluoro or methyl or R10a and R10b are taken together to form a carbonyl; each R11a and R11b is independently H, fluoro or methyl or R10a and R10b are taken together to form a carbonyl; Q is a substituted or unsubstituted aryl; Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group; Q is a substituted or unsubstituted phenyl or pyridyl group; Q is a phenyl or pyridyl group substituted with at least one methyl group; Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C1-C8 alkyl, halo or perhaloalkyl moiety; Q is a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclyl; Q is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group; Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group; Q is an unsubstituted cycloalkyl or an unsubstituted heterocyclyl; Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety; Q is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group; Q is selected from the group consisting of:





wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, aminoacyl or aminocarbonylamino; Q is substituted with no more than one R9 group; Q is substituted with only one R9 group; Q is selected from the group consisting of:





and wherein R9 is connected to Q ortho or para to the position at which Q is connected to the carbon bearing R8e and R8f; Q is





and

R9 is connected to Q para to the position at which Q is connected to the carbon bearing R8e and R8f;

Q is substituted with two R9 groups; Q is selected from the group consisting of:








wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, aminoacyl or aminocarbonylamino; Q is substituted with no more than one R9 group; Q is substituted with only one R9 group; Q is substituted with two R9 groups; each R9 is independently a substituted or unsubstituted C1-C4 alkyl, halo, trifluoromethyl or hydroxyl; each R9 is independently methyl, —CH2OH, isopropyl, halo, trifluoromethyl or hydroxyl; Q is selected from the group consisting of:








Q is selected from the group consisting of:





Q is selected from the group consisting of:





Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; Q is selected from the group consisting of:





R1 is an unsubstituted alkyl;

R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b are each H; each X7, X8, X9 and X10 is independently N or CH; each R8a, R8b, R8c, R8d, R8e and R8f is independently H, C1-C4 alkyl or hydroxyl; Q is a substituted or unsubstituted aryl; R1 is an unsubstituted alkyl; R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b are each H; each X7, X8, X9 and X10 is independently N or CH; each R8a, R8b, R8c, R8d, R8e and R8f is independently H or C1-C4 alkyl or is taken together with a geminal R8 to form a methylene or a substituted methylene; Q is a substituted or unsubstituted aryl; at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a geminal R8 to form a methylene or a substituted methylene; R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b are each H; each X7, X8, X9 and X10 is independently N or CH; each R8a, R8b, R8c, R8d, R8e and R8f is independently H or C1-C4 alkyl or is taken together with a vicinal R8 to form a bond; Q is a substituted or unsubstituted aryl; at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 to form a bond; Q is a substituted or unsubstituted phenyl or pyridyl group; Q is a phenyl or pyridyl group substituted with at least one methyl group; R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl; each R2a and R2b is independently H, unsubstituted C1-C8 alkyl or halo; each R3a and R3b is independently H or halo; each X7, X8, X9 and X10 is CR4; each R10a, R10b, R11a and R11b is independently H or methyl; Q is a substituted or unsubstituted aryl; Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group; Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C1-C8 alkyl, halo or perhaloalkyl moiety; R4 is H, halo, pyridyl, methyl or trifluoromethyl; R1 is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl; each R2a, R2b, R3a and R3b is independently H or halo; each R10a, R10b, R11a, R11b is independently H or methyl; each R4 is independently H, halo, C1-C8 perhaloalkyl, substituted or an unsubstituted C1-C8 alkyl; each R8a, R8b, R8c, R8d, R8e and R8f is H; Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety; R1 is a methyl; at least one of X7, X8, X9 and X10 is CR4 and each R4 is independently H, halo, methyl or trifluoromethyl; Q is substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group; each R2a and R2b is independently H, a substituted or unsubstituted C1-C8 alkyl or R2a and R2b are taken together to form a carbonyl moiety; each R3a and R3b is independently H, a substituted or unsubstituted C1-C8 alkyl or R3a and R3b are taken together to form a carbonyl moiety; each R4 is independently H, halo or substituted or unsubstituted C1-C8 alkyl; each R8a, R8b, R8c, R8d, R8e and R8f is H; each R10a and R10b is independently H, halo, a substituted or unsubstituted C1-C8 alkyl or R10a and R10b are taken together to form a carbonyl (═O); each R11a and R11b is independently H, halo, a substituted or unsubstituted C1-C8 alkyl or R11a and R11b are taken together to form a carbonyl (═O); Q is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group; Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group; at least one of X7, X8, X9 and X10 is CR4 and each R4 is independently H, halo or methyl.

Method of modulating a histamine receptor in an individual are provided, comprising administering to an individual in need thereof a compound as detailed herein.
A pharmaceutical composition comprising a compound as detailed herein and a pharmaceutically acceptable carrier are also provided.
Kits are also described, such as kits comprising a compound as detailed herein and instructions for use.
Methods of treating a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition are also provided, comprising administering to an individual in need thereof a low dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof. A method of treating (i) a psychotic disorder, (ii) a psychotic disorder in an individual who is also in need of improved cognition or (iii) a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition is also provided comprising administering to an individual in need thereof a high dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof. Use of a low dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition is also provided. Use of a high dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a (i) psychotic disorder, (ii) a psychotic disorder in an individual who is also in need of improved cognition or (iii) a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition is also provided. In one instance, a kit comprising a low dose of a compound and instructions for achieving a procognitive effect in the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition is provided. In another, a kit comprising a high dose of a compound as detailed herein or a pharmaceutically acceptable salt thereof, and instructions for achieving (i) a procognitive effect in the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition and (ii) an antipsychotic effect in the treatment of a psychotic disorder; a psychotic disorder in an individual who is also in need of improved cognition or a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition is provided.


DETAILED DESCRIPTION OF THE INVENTION
Definitions
For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human.
As used herein, the term “aminergic G protein-coupled receptors” refers to a family of transmembrane proteins involved in cellular communication. Aminergic G protein coupled receptors are activated by biogenic amines and represent a subclass of the superfamily of G protein coupled receptors, which are structurally characterized by seven transmembrane helices. Aminergic G protein-coupled receptors include but are not limited to adrenergic receptors, serotonin receptors, dopamine receptors, histamine receptors and imidazoline receptors.
As used herein, the term “adrenergic receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to an adrenergic receptor or reduces or eliminates or increases or enhances or mimics an activity of an adrenergic receptor. As such, an “adrenergic receptor modulator” encompasses both an adrenergic receptor antagonist and an adrenergic receptor agonist. In some aspects, the adrenergic receptor modulator binds to or inhibits binding to a ligand to an α1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or a α2-adrenergic receptor (e.g., α2A, α2B and/or α2C) and/or reduces or eliminates or increases or enhances or mimics an activity of a α1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or a α2-adrenergic receptor (e.g., α2A, α2B and/or α2C) in a reversible or irreversible manner. In some aspects, the adrenergic receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some aspects, the adrenergic receptor modulator reduces an activity of an adrenergic receptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the adrenergic receptor modulator or compared to the corresponding activity in other subjects not receiving the adrenergic receptor modulator. In some aspects, the adrenergic receptor modulator enhances an activity of an adrenergic receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the adrenergic receptor modulator or compared to the corresponding activity in other subjects not receiving the adrenergic receptor modulator. In some aspects, the adrenergic receptor modulator is capable of binding to the active site of an adrenergic receptor (e.g., a binding site for a ligand). In some embodiments, the adrenergic receptor modulator is capable of binding to an allosteric site of an adrenergic receptor.
As used herein, the term “dopamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a dopamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine receptor. As such, a “dopamine receptor modulator” encompasses both a dopamine receptor antagonist and a dopamine receptor agonist. In some aspects, the dopamine receptor modulator binds to or inhibits binding of a ligand to a dopamine-1 (D1) and/or a dopamine-2 (D2) receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine-1 (D1) and/or a dopamine-2 (D2) receptor in a reversible or irreversible manner. Dopamine D2 receptors are divided into two categories, D2L and D2S, which are formed from a single gene by differential splicing. D2L receptors have a longer intracellular domain than D2S. In some embodiments, the dopamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the dopamine receptor modulator reduces an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator. In some embodiments, the dopamine receptor modulator enhances an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator. In some embodiments, the dopamine receptor modulator is capable of binding to the active site of a dopamine receptor (e.g., a binding site for a ligand). In some embodiments, the dopamine receptor modulator is capable of binding to an allosteric site of a dopamine receptor.
As used herein, the term “serotonin receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a serotonin receptor or reduces or eliminates or increases or enhances or mimics an activity of a serotonin receptor. As such, a “serotonin receptor modulator” encompasses both a serotonin receptor antagonist and a serotonin receptor agonist. In some embodiments, the serotonin receptor modulator binds to or inhibits binding of a ligand to a 5-HT1A and/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a 5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor or reduces or eliminates or increases or enhances or mimics an activity of a 5-HT1A and/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a 5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor in a reversible or irreversible manner. In some embodiments, the serotonin receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the serotonin receptor modulator reduces an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator. In some embodiments, the serotonin receptor modulator enhances an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator. In some embodiments, the serotonin receptor modulator is capable of binding to the active site of a serotonin receptor (e.g., a binding site for a ligand). In some embodiments, the serotonin receptor modulator is capable of binding to an allosteric site of a serotonin receptor.
As used herein, the term “histamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a histamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine receptor. As such, a “histamine receptor modulator” encompasses both a histamine receptor antagonist and a histamine receptor agonist. In some embodiments, the histamine receptor modulator binds to or inhibits binding of a ligand to a histamine H1 and/or H2 and/or H3 receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine H1 and/or H2 and/or H3 receptor in a reversible or irreversible manner. In some embodiments, the histamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the histamine receptor modulator reduces an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator. In some embodiments, the histamine receptor modulator enhances an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator. In some embodiments, the histamine receptor modulator is capable of binding to the active site of a histamine receptor (e.g., a binding site for a ligand). In some embodiments, the histamine receptor modulator is capable of binding to an allosteric site of a histamine receptor.
Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human, bovine, primate, equine, canine, feline, porcine, and ovine animals. Thus, the invention finds use in both human medicine and in the veterinary context, including use in agricultural animals and domestic pets. The individual may be a human who has been diagnosed with or is suspected of having a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who exhibits one or more symptoms associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who has a mutated or abnormal gene associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who is genetically or otherwise predisposed to developing a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder.
As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, such as a clinical result. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In one variation, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. Preferably, treatment of a disease or condition with a compound of the invention or a pharmaceutically acceptable salt thereof is accompanied by no or fewer side effects than are associated with currently available therapies for the disease or condition and/or improves the quality of life of the individual.
As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. For example, a method that “delays” development of Alzheimer's disease is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. For example, Alzheimer's disease development can be detected using standard clinical techniques, such as routine neurological examination, patient interview, neuroimaging, detecting alterations of levels of specific proteins in the serum or cerebrospinal fluid (e.g., amyloid peptides and Tau), computerized tomography (CT) or magnetic resonance imaging (MRI). Similar techniques are known in the art for other diseases and conditions. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.
As used herein, an “at risk” individual is an individual who is at risk of developing a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder that can be treated with a compound of the invention. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). These risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (i.e., hereditary) considerations, and environmental exposure. For example, individuals at risk for Alzheimer's disease include, e.g., those having relatives who have experienced this disease and those whose risk is determined by analysis of genetic or biochemical markers. Genetic markers of risk for Alzheimer's disease include mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Other markers of risk are mutations in the presenilin genes (e.g., PS1 or PS2), ApoE4 alleles, family history of Alzheimer's disease, hypercholesterolemia and/or atherosclerosis. Other such factors are known in the art for other diseases and conditions.
As used herein, the term “pro-cognitive” includes but is not limited to an improvement of one or more mental processes such as memory, attention, perception and/or thinking, which may be assessed by methods known in the art.
As used herein, the term “neurotrophic” effects includes but is not limited to effects that enhance neuron function such as growth, survival and/or neurotransmitter synthesis.
As used herein, the term “cognitive disorders” refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and/or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and/or thinking). These disorders include pathogen-induced cognitive dysfunction, e.g. HIV associated cognitive dysfunction and Lyme disease associated cognitive dysfunction. Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, ADD, ADHD, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI).
As used herein, the term “psychotic disorders” refers to and intends mental diseases or conditions that are believed to cause or do cause abnormal thinking and perceptions. Psychotic disorders are characterized by a loss of reality which may be accompanied by delusions, hallucinations (perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space), personality changes and/or disorganized thinking. Other common symptoms include unusual or bizarre behavior, as well as difficulty with social interaction and impairment in carrying out the activities of daily living. Exemplary psychotic disorders are schizophrenia, bipolar disorders, psychosis, anxiety and depression.
As used herein, the term “neurotransmitter-mediated disorders” refers to and intends diseases or conditions that are believed to involve or be associated with or do involve or are associated with abnormal levels of neurotransmitters such as histamine, serotonin, dopamine, norepinephrine or impaired function of aminergic G protein-coupled receptors. Exemplary neurotransmitter-mediated disorders include spinal cord injury, diabetic neuropathy, allergic diseases and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited, to Alzheimer's disease, Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia, anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression and a variety of allergic diseases.
As used herein, the term “neuronal disorders” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function. Exemplary neuronal indications include neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), post-concussion syndrome, post-traumatic stress disorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, anxiety or depression.
As used herein, the term “neuron” represents a cell of ectodermal embryonic origin derived from any part of the nervous system of an animal. Neurons express well-characterized neuron-specific markers, including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2, and class III tubulin. Included as neurons are, for example, hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory, sympathetic, septal cholinergic, and cerebellar neurons.
As used herein, the term “neurite outgrowth” or “neurite activation” refers to the extension of existing neuronal processes (e.g., axons and dendrites) and the growth or sprouting of new neuronal processes (e.g., axons and dendrites). Neurite outgrowth or neurite activation may alter neural connectivity, resulting in the establishment of new synapses or the remodeling of existing synapses.
As used herein, the term “neurogenesis” refers to the generation of new nerve cells from undifferentiated neuronal progenitor cells, also known as multipotential neuronal stem cells. Neurogenesis actively produces new neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/or other neural lineages. Much neurogenesis occurs early in human development, though it continues later in life, particularly in certain localized regions of the adult brain.
As used herein, the term “neural connectivity” refers to the number, type, and quality of connections (“synapses”) between neurons in an organism. Synapses form between neurons, between neurons and muscles (a “neuromuscular junction”), and between neurons and other biological structures, including internal organs, endocrine glands, and the like. Synapses are specialized structures by which neurons transmit chemical or electrical signals to each other and to non-neuronal cells, muscles, tissues, and organs. Compounds that affect neural connectivity may do so by establishing new synapses (e.g., by neurite outgrowth or neurite activation) or by altering or remodeling existing synapses. Synaptic remodeling refers to changes in the quality, intensity or type of signal transmitted at particular synapses.
As used herein, the term “neuropathy” refers to a disorder characterized by altered function and/or structure of motor, sensory, and autonomic neurons of the nervous system, initiated or caused by a primary lesion or other dysfunction of the nervous system. Patterns of peripheral neuropathy include polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy. The most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs. A radiculopathy involves spinal nerve roots, but if peripheral nerves are also involved the term radiculoneuropathy is used. The form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, e.g. large fiber or small fiber peripheral neuropathy. Central neuropathic pain can occur in spinal cord injury, multiple sclerosis, and some strokes, as well as fibromyalgia. Neuropathy may be associated with varying combinations of weakness, autonomic changes and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle may also be seen. Sensory symptoms encompass loss of sensation and “positive” phenomena including pain. Neuropathies are associated with a variety of disorders, including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiple sclerosis, and herpes zoster infection, as well as with spinal cord injury and other types of nerve damage.
As used herein, the term “Alzheimer's disease” refers to a degenerative brain disorder characterized clinically by progressive memory deficits, confusion, behavioral problems, inability to care for oneself, gradual physical deterioration and, ultimately, death. Histologically, the disease is characterized by neuritic plaques, found primarily in the association cortex, limbic system and basal ganglia. The major constituent of these plaques is amyloid beta peptide (Aβ), which is the cleavage product of beta amyloid precursor protein (βAPP or APP). APP is a type I transmembrane glycoprotein that contains a large ectopic N-terminal domain, a transmembrane domain and a small cytoplasmic C-terminal tail. Alternative splicing of the transcript of the single APP gene on chromosome 21 results in several isoforms that differ in the number of amino acids. A13 appears to have a central role in the neuropathology of Alzheimer's disease. Familial forms of the disease have been linked to mutations in APP and the presenilin genes (Tanzi et al., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med., 28:255-258). Diseased-linked mutations in these genes result in increased production of the 42-amino acid form of Aβ, the predominant form found in amyloid plaques. Mitochondrial dysfunction has also been reported to be an important component of Alzheimer's disease (Bubber et al., Mitochondrial abnormalities in Alzheimer brain: Mechanistic Implications, Ann Neurol., 2005, 57(5), 695-703; Wang et al., Insights into amyloid-β-induced mitochondrial dysfunction in Alzheimer disease, Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al., Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol., 2002, 53, 341-385; and Reddy et al., Are mitochondria critical in the pathogenesis of Alzheimer's disease?, Brain Res Rev. 2005, 49(3), 618-32). It has been proposed that mitochondrial dysfunction has a causal relationship with neuronal function (including neurotransmitter synthesis and secretion) and viability. Compounds which stabilize mitochondria may therefore have a beneficial impact on Alzheimer's patients.
As used herein, the term “Huntington's disease” refers to a fatal neurological disorder characterized clinically by symptoms such as involuntary movements, cognition impairment or loss of cognitive function and a wide spectrum of behavioral disorders. Common motor symptoms associated with Huntington's disease include chorea (involuntary writhing and spasming), clumsiness, and progressive loss of the abilities to walk, speak (e.g., exhibiting slurred speech) and swallow. Other symptoms of Huntington's disease can include cognitive symptoms such as loss of intellectual speed, attention and short-term memory and/or behavioral symptoms that can span the range of changes in personality, depression, irritability, emotional outbursts and apathy. Clinical symptoms typically appear in the fourth or fifth decade of life. Huntington's disease is a devastating and often protracted illness, with death usually occurring approximately 10-20 years after the onset of symptoms. Huntington's disease is inherited through a mutated or abnormal gene encoding an abnormal protein called the mutant huntingtin protein; the mutated huntingtin protein produces neuronal degeneration in many different regions of the brain. The degeneration focuses on neurons located in the basal ganglia, structures deep within the brain that control many important functions including coordinating movement, and on neurons on the outer surface of the brain or cortex, which controls thought, perception and memory.
“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote a progressive neurodegenerative disease that affects upper motor neurons (motor neurons in the brain) and/or lower motor neurons (motor neurons in the spinal cord) and results in motor neuron death. As used herein, the term “ALS” includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS).
The term “Parkinson's disease” as used herein refers to any medical condition wherein an individual experiences one or more symptoms associated with Parkinson's disease, such as without limitation one or more of the following symptoms: rest tremor, cogwheel rigidity, bradykinesia, postural reflex impairment, symptoms having good response to 1-dopa treatment, the absence of prominent oculomotor palsy, cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia. In a specific embodiment, the present invention is utilized for the treatment of a dopaminergic dysfunction-related disorder. In a specific embodiment, the individual with Parkinson's disease has a mutation or polymorphism in a synuclein, parkin or NURR1 nucleic acid that is associated with Parkinson's disease. In one embodiment, the individual with Parkinson's disease has defective or decreased expression of a nucleic acid or a mutation in a nucleic acid that regulates the development and/or survival of dopaminergic neurons.
As used herein, the term “canine cognitive dysfunction syndrome,” or “CCDS” refers to an age-related deterioration of mental function typified by multiple cognitive impairments that affect an afflicted canine's ability to function normally. The decline in cognitive ability that is associated with CCDS cannot be completely attributed to a general medical condition such as neoplasia, infection, sensory impairment, or organ failure. Diagnosis of CCDS in canines, such as dogs, is generally a diagnosis of exclusion, based on thorough behavior and medical histories and the presence of clinical symptoms of CCDS that are unrelated to other disease processes. Owner observation of age-related changes in behavior is a practical means used to detect the possible onset of CCDS in aging domestic dogs. A number of laboratory cognitive tasks may be used to help diagnose CCDS, while blood counts, chemistry panels and urinalysis can be used to rule out other underlying diseases that could mimic the clinical symptoms of CCDS. Symptoms of CCDS include memory loss, which in domestic dogs may be manifested by disorientation and/or confusion, decreased or altered interaction with family members and/or greeting behavior, changes in sleep-wake cycle, decreased activity level, and loss of house training or frequent, inappropriate elimination. A canine suffering from CCDS may exhibit one or more of the following clinical or behavioral symptoms: decreased appetite, decreased awareness of surroundings, decreased ability to recognize familiar places, people or other animals, decreased hearing, decreased ability to climb up and down stairs, decreased tolerance to being alone, development of compulsive behavior or repetitive behaviors or habits, circling, tremors or shaking, disorientation, decreased activity level, abnormal sleep wake cycles, loss of house training, decreased or altered responsiveness to family members, and decreased or altered greeting behavior. CCDS can dramatically affect the health and well-being of an afflicted canine. Moreover, the companionship offered by a pet with CCDS can become less rewarding as the severity of the disease increases and its symptoms become more severe.
As used herein, the term “age-associated memory impairment” or “AAMI” refers to a condition that may be identified as GDS stage 2 on the global deterioration scale (GDS) (Reisberg, et al. (1982) Am. J. Psychiatry 139: 1136-1139) which differentiates the aging process and progressive degenerative dementia in seven major stages. The first stage of the GDS is one in which individuals at any age have neither subjective complaints of cognitive impairment nor objective evidence of impairment. These GDS stage 1 individuals are considered normal. The second stage of the GDS applies to those generally elderly persons who complain of memory and cognitive functioning difficulties such as not recalling names as well as they could five or ten years previously or not recalling where they have placed things as well as they could five or ten years previously. These subjective complaints appear to be very common in otherwise normal elderly individuals. AAMI refers to persons in GDS stage 2, who may differ neurophysiologically from elderly persons who are normal and free of subjective complaints, i.e., GDS stage 1. For example, AAMI subjects have been found to have more electrophysiologic slowing on a computer analyzed EEG than GDS stage 1 elderly persons (Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15: 85-90).
As used herein, the term “mild cognitive impairment” or “MCI” refers to a type of cognitive disorder characterized by a more pronounced deterioration in cognitive functions than is typical for normal age-related decline. As a result, elderly or aged patients with MCI have greater than normal difficulty performing complex daily tasks and learning, but without the inability to perform normal social, everyday, and/or professional functions typical of patients with Alzheimer's disease, or other similar neurodegenerative disorders eventually resulting in dementia. MCI is characterized by subtle, clinically manifest deficits in cognition, memory, and functioning, amongst other impairments, which are not of sufficient magnitude to fulfill criteria for diagnosis of Alzheimer's disease or other dementia. MCI also encompasses injury-related MCI, defined herein as cognitive impairment resulting from certain types of injury, such as nerve injury (i.e., battlefield injuries, including post-concussion syndrome, and the like), neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemo brain” and the like), and tissue damage resulting from physical injury or other neurodegeneration, which is separate and distinct from mild cognitive impairment resulting from stroke, ischemia, hemorrhagic insult, blunt force trauma, and the like.
As used herein, the term “traumatic brain injury” or “TBI” refers to a brain injury caused by a sudden trauma, such as a blow or jolt or a penetrating head injury, which disrupts the function or damages the brain. Symptoms of TBI can range from mild, moderate to severe and can significantly affect many cognitive (deficits of language and communication, information processing, memory, and perceptual skills), physical (ambulation, balance, coordination, fine motor skills, strength, and endurance), and psychological skills.
“Neuronal death mediated ocular disease” intends an ocular disease in which death of the neuron is implicated in whole or in part. The disease may involve death of photoreceptors. The disease may involve retinal cell death. The disease may involve ocular nerve death by apoptosis. Particular neuronal death mediated ocular diseases include but are not limited to macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.
As used herein, the term “macular degeneration” includes all forms and classifications of macular degeneration known in the art, including, but not limited to diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium. The term thus encompasses disorders such as age-related macular degeneration (ARMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life. Other maculopathies include North Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt's disease, pattern dystrophy, Best disease, and Malattia Leventinese.
As used herein, the term “autism” refers to a brain development disorder that impairs social interaction and communication and causes restricted and repetitive behavior, typically appearing during infancy or early childhood. The cognitive and behavioral defects are thought to result in part from altered neural connectivity. Autism encompasses related disorders sometimes referred to as “autism spectrum disorder,” as well as Asperger syndrome and Rett syndrome.
As used herein, the term “nerve injury” or “nerve damage” refers to physical damage to nerves, such as avulsion injury (i.e., where a nerve or nerves have been torn or ripped) or spinal cord injury (i.e., damage to white matter or myelinated fiber tracts that carry sensation and motor signals to and from the brain). Spinal cord injury can occur from many causes, including physical trauma (i.e., car accidents, sports injuries, and the like), tumors impinging on the spinal column, developmental disorders, such as spina bifida, and the like.
As used herein, the term “myasthenia gravis” or “MG” refers to a non-cognitive neuromuscular disorder caused by immune-mediated loss of acetylcholine receptors at neuromuscular junctions of skeletal muscle. Clinically, MG typically appears first as occasional muscle weakness in approximately two-thirds of patients, most commonly in the extraocular muscles. These initial symptoms eventually worsen, producing drooping eyelids (ptosis) and/or double vision (diplopia), often causing the patient to seek medical attention. Eventually, many patients develop general muscular weakness that may fluctuate weekly, daily, or even more frequently. Generalized MG often affects muscles that control facial expression, chewing, talking, swallowing, and breathing; before recent advances in treatment, respiratory failure was the most common cause of death.
As used herein, the term “Guillain-Barré syndrome” refers to a non-cognitive disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs. In many instances the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until certain muscles cannot be used at all and, when severe, the patient is almost totally paralyzed. In these cases the disorder is life threatening—potentially interfering with breathing and, at times, with blood pressure or heart rate—and is considered a medical emergency. Most patients, however, recover from even the most severe cases of Guillain-Barré syndrome, although some continue to have a certain degree of weakness.
As used herein, the term “multiple sclerosis” or “MS” refers to an autoimmune condition in which the immune system attacks the central nervous system (CNS), leading to demyelination of neurons. It may cause numerous symptoms, many of which are non-cognitive, and often progresses to physical disability. MS affects the areas of the brain and spinal cord known as the white matter. White matter cells carry signals between the grey matter areas, where the processing is done, and the rest of the body. More specifically, MS destroys oligodendrocytes which are the cells responsible for creating and maintaining a fatty layer, known as the myelin sheath, which helps the neurons carry electrical signals. MS results in a thinning or complete loss of myelin and, less frequently, the cutting (transection) of the neuron's extensions or axons. When the myelin is lost, the neurons can no longer effectively conduct their electrical signals. Almost any neurological symptom can accompany the disease. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Most people are first diagnosed with relapsing-remitting MS but develop secondary-progressive MS (SPMS) after a number of years. Between attacks, symptoms may go away completely, but permanent neurological problems often persist, especially as the disease advances.
As used herein, the term “schizophrenia” refers to a chronic, mental disorder characterized by one or more positive symptoms (e.g., delusions and hallucinations) and/or negative symptoms (e.g., blunted emotions and lack of interest) and/or disorganized symptoms (e.g., disorganized thinking and speech or disorganized perception and behavior). Schizophrenia as used herein includes all forms and classifications of schizophrenia known in the art, including, but not limited to catatonic type, hebephrenic type, disorganized type, paranoid type, residual type or undifferentiated type schizophrenia and deficit syndrome and/or those described in American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington D.C., 2000 or in International Statistical Classification of Diseases and Related Health Problems, or otherwise known to those of skill in the art.
“Cognitive impairment associated with schizophrenia” or “CIAS” includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits are believed to be linked to impairment in functional status (e.g., social behavior, work performance, and activities of daily living).
As used herein “geroprotective activity” or “geroprotector” means a biological activity that slows down ageing and/or prolongs life and/or increases or improves the quality of life via a decrease in the amount and/or the level of intensity of pathologies or conditions that are not life-threatening but are associated with the aging process and which are typical for elderly people. Pathologies or conditions that are not life-threatening but are associated with the aging process include such pathologies or conditions as loss of sight (cataract), deterioration of the dermatohairy integument (alopecia), and an age-associated decrease in weight due to the death of muscular and/or fatty cells.
As used herein, attention-deficit hyperactivity disorder (ADHD) is the most common child neuropsychiatric condition present in school-aged children, affecting about 5-8% of this population. ADHD refers to a chronic disorder that initially manifests in childhood and is characterized by hyperactivity, impulsivity, and/or inattention. ADHD is characterized by persistent patterns of inattention and/or impulsivity-hyperactivity that are much more extreme than is observed in individuals at the same developmental level or stage. There is considerable evidence, from family and twin studies, that ADHD has a significant genetic component. This disorder is thought to be due to an interaction of environmental and genetic factors. ADHD includes all known types of ADHD. For example, Diagnostic & Statistical Manual for Mental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD, Combined Type which is characterized by both inattention and hyperactivity-impulsivity symptoms; 2. ADHD, Predominantly Inattentive Type which is characterized by inattention but not hyperactivity-impulsivity symptoms; and 3. ADHD, Predominantly Hyperactive-Impulsive Type which is characterized by Hyperactivity-impulsivity but not inattention symptoms.
As used herein, attention-deficit disorder (ADD) refers to a disorder in processing neural stimuli that is characterized by distractibility and impulsivity that can result in inability to control behavior and can impair an individual's social, academic, or occupational function and development. ADD may be diagnosed by known methods, which may include observing behavior and diagnostic interview techniques.
As used herein “allergic disease” refers to a disorder of the immune system which is characterized by excessive activation of mast cells and basophils and production of IgE immunoglobulins, resulting in an extreme inflammatory response. It represents a form of hypersensitivity to an environmental substance known as allergen and is an acquired disease. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees. Allergic reactions are accompanied by an excessive release of histamines, and can thus be treated with antihistaminic agents.
As used herein, by “combination therapy” is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and another compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances. In various embodiments, treatment with a combination therapy may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of a single compound of the invention alone. In some embodiments, a lower amount of each compound is used as part of a combination therapy compared to the amount generally used for individual therapy. Preferably, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a compound in a combination therapy than the amount generally used for individual compound or therapy. Preferably, the use of a small amount of compound results in a reduction in the number, severity, frequency, and/or duration of one or more side-effects associated with the compound.
As used herein, the term “effective amount” intends such amount of a compound of the invention which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.
As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).
As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
“Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
“Alkyl” refers to and includes saturated linear, branched, or cyclic univalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C1-C8 alkyl”). When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkyl”). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
“Alkylene” refers to the same residues as alkyl, but having bivalency. Examples of alkylene include methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), butylene (—CH2CH2CH2CH2—) and the like.
“Alkenyl” refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms. Examples of alkenyl include but are not limited to —CH2—CH═CH—CH3 and —CH2—CH2-cyclohexenyl, where the ethyl group of the latter example can be attached to the cyclohexenyl moiety at any available position on the ring. Cycloalkenyl is a subset of alkenyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
“Alkynyl” refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and preferably having from 2 to 10 carbon atoms and more preferably 3 to 8 carbon atoms.
“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkenyl” refers to alkenyl group having from 1 to 5 substituents s including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkynyl” refers to alkynyl groups having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the rings can be aryl or heteroaryl. A heterocycle having more than one ring where at least one ring is aromatic may be connected to the parent structure at either a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.
“Substituted heterocyclic” or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. In one variation, a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.
“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
“Heteroaryl” or “HetAr” refers to an unsaturated aromatic heterocyclic group having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
“Substituted aryl” refers to an aryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Aralkyl” refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. Preferably, an aralkyl is connected to the parent structure via the alkyl moiety. In one variation, an aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety. A “substituted aralkyl” refers to a residue in which an aryl moiety is attached to a substituted alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. When an aralkyl is connected to the parent structure via the alkyl moiety, it may also be referred to as an “alkaryl”. More particular alkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety (a “C1-C3 alkaryl”).
“Alkoxy” refers to the group alkyl-O—, which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxy refers to the group “alkynyl-O—”. “Substituted alkoxy” refers to the group substituted alkyl-O.
“Unsubstituted amino” refers to the group —NH2.
“Substituted amino” refers to the group —NRaRb, where either (a) each Ra and Rb group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, provided that both Ra and Rb groups are not H; or (b) Ra and Rb are joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
“Acylamino” refers to the group —C(O)NRaRb where Ra and Rb are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or Ra and Rb groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
“Aminocarbonylalkoxy” refers to the group —NRaC(O)ORb where each Ra and Rb group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl.
“Aminoacyl” refers to the group —NRaC(O)Rb where each Ra and Rb group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. Preferably, Ra is H or alkyl.
“Aminosulfonyl” refers to the groups —NRSO2-alkyl, —NRSO2 substituted alkyl, —NRSO2-alkenyl, —NRSO2-substituted alkenyl, —NRSO2-alkynyl, —NRSO2-substituted alkynyl, —NRSO2-cycloalkyl, —NRSO2-substituted cycloalkyl, —NRSO2-aryl, —NRSO2-substituted aryl, —NRSO2-heteroaryl, —NRSO2-substituted heteroaryl, —NRSO2-heterocyclic, and —NRSO2-substituted heterocyclic, where R is H or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Sulfonylamino” refers to the groups —SO2NH2, —SO2NR-alkyl, —SO2NR-substituted alkyl, —SO2NR-alkenyl, —SO2NR-substituted alkenyl, —SO2NR-alkynyl, —SO2NR-substituted alkynyl, —SO2NR-aryl, —SO2NR-substituted aryl, —SO2NR-heteroaryl, —SO2NR-substituted heteroaryl, —SO2NR-heterocyclic, and —SO2NR-substituted heterocyclic, where R is H or alkyl, or —SO2NR2, where the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring.
“Sulfonyl” refers to the groups —SO2-alkyl, —SO2-substituted alkyl, —SO2-alkenyl, —SO2-substituted alkenyl, —SO2-alkynyl, —SO2-substituted alkynyl, —SO2-aryl, —SO2-substituted aryl, —SO2-heteroaryl, —SO2-substituted heteroaryl, —SO2-heterocyclic, and —SO2-substituted heterocyclic.
“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH2)n—OR where R is a substituted or unsubstituted alkyl and n is an integer from 1 to 100, more preferably n is an integer from 1 to 10 or 1 to 5.
“Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each H is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (—CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF3).
“Carbonyl” refers to the group C═O.
“Cyano” refers to the group —CN.
“Oxo” refers to the moiety ═O.
“Nitro” refers to the group —NO2.
“Thioalkyl” refers to the groups —S-alkyl.
“Alkylsulfonylamino” refers to the groups —R1SO2NRaRb where Ra and Rb are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or the Ra and Rb groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring and R1 is an alkyl group.
“Carbonylalkoxy” refers to as used herein refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.
“Geminal” refers to the relationship between two moieties that are attached to the same atom. For example, in the residue —CH2—CHR1R2, R1 and R2 are geminal and R1 may be referred to as a geminal R group to R2.
“Vicinal” refers to the relationship between two moieties that are attached to adjacent atoms. For example, in the residue —CHR1—CH2R2, R1 and R2 are vicinal and R1 may be referred to as a vicinal R group to R2.
A composition of “substantially pure” compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure S compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the R form of the compound.
Compounds of the Invention
Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and the appended claims. The invention includes the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans) or E/Z isomers, salts and solvates of the compounds described herein, as histamine receptor modulators, as well as methods of making such compounds.
The invention embraces compounds of the formula (I):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
provided that the compound is other than a compound in Table 1;
or a salt or solvate thereof.
Compounds of the general formula (I) are described as new histamine receptor modulators. Compounds of the invention may also find use in treating neurodegenerative diseases.
In one variation, the compounds of the invention, pharmaceutical compositions thereof, isolated forms thereof and methods of using and administering the compounds detailed herein, encompass any of the compounds of Formula (I), including those listed in Table 1 or a salt thereof.
In one variation, the compound of the formula (I) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (I); each R2 independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl; Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; provided that the compound is other than a compound in Table 1; or a salt or solvate thereof. In one such variation, the compounds, pharmaceutical compositions thereof, isolated forms thereof and methods of using and administering the compounds detailed herein, encompass any of the compounds of Formula (I), including those listed in Table 1 or a salt thereof.
In another variation, the compound of the invention is of the formula (I), where each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety. In yet another variation, the compound is of the formula (I), where each R2a, R2b, R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety and each R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety (e.g. cyclopropyl). In another variation, the compound is of the formula (I), where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or a unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The invention also embraces compounds of the formula (A):




or a salt or solvate thereof,
wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with a geminal R8(a-d) to form a moiety of the formula —OCH2CH2O—, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety;
each R8g and R8h is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl,-substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, C1-C8 perhaloalkyl, carboxy, or carbonylalkoxy and the bond indicates the presence of either an E or Z double bond configuration, or R8g and R8h are taken together to form a bond; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl.
In one variation, the compound of the formula (A) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (A); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c and R8d is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene; R8g is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8h and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety and the bond indicates the presence of either an E or Z double bond configuration; R8h is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8g and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The invention further embraces compounds of the formula (A-1):




or a salt or solvate thereof,
wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene;
R8g is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8h and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety and the bond indicates the presence of either an E or Z double bond configuration;
R8h is H, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8g and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl.
In one variation, the compound of the formula (A-1) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (A-1); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c and R8d is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene; R8g is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8h and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety and the bond indicates the presence of either an E or Z double bond configuration; R8h is H, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C2-C8 alkenyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8g and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The substituent groups R1, R2a, R2b, R3a, R3b, R8a, R8b, R8c, R8d, R8g, R8h, R10a, R10b, R11a, R11b, m, q, Q, X7, X8, X9, and X10 described herein as suitable for compounds of formula (A) are also suitable for compounds of formulae (A-1). Variations of formula (A) detailed throughout, where applicable, apply to formula (A-1) the same as if each and every variation were specifically and individually listed for formula (A-1).
The invention also embraces compounds of the formula (B):




or a salt or solvate thereof;
wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety;
each Rga and Rha is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxy, or carbonylalkoxy; or Rga and Rha may be taken together to represent a bond;
Rgb and Rhb are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl.
In one variation, the compound of the formula (B) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (B); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c and R8d is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene; each of Rga and Rha is independently H, hydroxyl, or C1-C8 alkyl; or Rga and Rha may be taken together to represent a bond; Rgb and Rhb are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The invention also embraces compounds of the formula (Ia):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or R8e and R8f are taken together to form a moiety of the formula —OCH2CH2O—, a methylene or a substituted methylene, or R8e and R8f are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, the compound of the formula (Ia) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (Ia); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety or is taken together with a geminal R8 to form a methylene or a substituted methylene; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.
In one variation, the compound of the invention is of the formula (Ia), where each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety. In another variation, the compound is of the formula (I), where each R2a, R2b, R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety and each R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety (e.g. cyclopropyl). In another variation, the compound is of the formula (Ia), where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or a unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The invention also embraces compounds of the formula (Ib):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, the compound of the formula (Ib) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, q and m are as defined for formula (Ib); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.
In one variation, the compound of the invention is of the formula (Ib), where each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety. In another variation, the compound is of the formula (I), where each R2a, R2b, R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety and each R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety (e.g. cyclopropyl). In another variation, the compound is of the formula (Ib), where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or a unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
The invention also embraces compound of the formula (Ic):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, the compound of the formula (Ic) is provided, where each X7, X8, X9, X10, R1, R10a, R10b, R11a, R11b, and m are as defined for formula (Ic); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.
In one variation, the compound of the invention is of the formula (Ic), where each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety. In another variation, the compound is of the formula (I), where each R2a, R2b, R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety and each R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety (e.g. cyclopropyl). In another variation, the compound is of the formula (Ic), where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or a unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. In another variation, the compound is of the formula (Ic), provided that when R8c and R8d are hydrogen and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, then Q is other than —NHR where R is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
In one embodiment, the compound is of the formula (Ic) where R8c and R8e are taken together to form a bond, each R8d and R8f is independently H, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or R8d and R8f are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety. In one embodiment, the compound is of the formula (C) and the bond indicates the presence of either an E or Z double bond configuration:




In one variation, the compound is of the formula (C), wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
R8d is H, C1-C8 perhaloalkyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with R8f and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety and the bond indicates the presence of either an E or Z double bond configuration;
R8f is H, C1-C8 perhaloalkyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with R8d and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, the compound of the formula (C) is provided, where each X7, X8, X9, X10, R1, R2a, R2b, R3a, R3b, R10a, R10b, R11a, R11b, q and m are as defined for formula (C); R8d is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8f and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety and the bond indicates the presence of either an E or Z double bond configuration; R8f is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 perhaloalkyl or is taken together with R8d and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.
In one variation, the compound is of the formula (C), wherein at least one of the X7, X8, X9 and X10 is CR4, where each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl. In another variation, each X7, X8, X9 and X10 is CR4. In another variation, one of X7, X8, X9 and X10 is CR4 and the others are CH. In another variation, two of X7, X8, X9 and X10 are CR4 and the others are CH. In one variation, at least one of X7, X8, X9 and X10 is CR4 where R4 is halo, C1-C8 perhaloalkyl or substituted or unsubstituted C1-C8 alkyl. In another variation, each X7, X8 and X10 is CH and X9 is CR4 where R4 is halo, C1-C8 perhaloalkyl or substituted or unsubstituted C1-C8 alkyl. In another variation, each X7, X8 and X10 is CH and X9 is CR4 where R4 is halo, e.g. chloro or fluoro. In another variation, each X7, X8 and X10 is CH and X9 is CR4 where R4 is unsubstituted C1-C8 alkyl, e.g. methyl. In another variation, each X7, X8 and X10 is CH and X9 is CR4 where R4 is unsubstituted C1-C8 perhaloalkyl, e.g. CF3. In one variation, the compound is of the formula (C), where Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl. In another variation, Q is substituted or unsubstituted heteroaryl, e.g. substituted or unsubstituted pyridyl. In another variation, Q is substituted or unsubstituted aryl, e.g. substituted or unsubstituted phenyl. In another variation, Q is phenyl substituted with one or more of the substituents selected from halo, C1-C8 alkyl, C1-C8 perhaloalkyl and alkoxy, e.g. 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-methoxyl-2-fluorophenyl, 4-methoxyl-3-fluorophenyl and 3-methoxy-4-fluorophenyl. In one variation, the compound is of the formula (C), where each R1, R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl. In another variation, R1 is substituted or unsubstituted C1-C8 alkyl, e.g. methyl. In another variation, each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is H. In another variation, R1 is substituted or unsubstituted C1-C8 alkyl, e.g. methyl, and each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is H. In one variation, the compound is of the formula (C), where each R8d and R8f is independently H, C1-C8 perhaloalkyl or substituted or unsubstituted C1-C8 alkyl. In another variation, each R8d and R8f is independently H or unsubstituted C1-C8 alkyl, e.g. methyl, ethyl and cyclopropyl. In another variation, the compound is of the formula (C) where each X7, X8 and X10 is CH and X9 is CR4 where R4 is halo, C1-C8 perhaloalkyl or substituted or unsubstituted C1-C8 alkyl (e.g. methyl), R1 is substituted or unsubstituted C1-C8 alkyl (e.g. methyl), each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is H, each R8d and R8f is independently H or unsubstituted C1-C8 alkyl, and Q is substituted or unsubstituted aryl, e.g. substituted or unsubstituted phenyl.
In one variation, compounds of the formula (X-1) are provided:




or a salt or solvate thereof, where R1, R4, R8f and Q are defined as for formula (C) and, where applicable, any variation thereof detailed herein. That is, variations of formula (C) detailed throughout, where applicable, apply to formula (X-1) the same as if each and every variation were specifically and individually listed for formula (X-1).

In one variation, compounds of the formula (X-1) are provided, or a salt or solvate thereof, where R1 is a substituted or unsubstituted C1-C8 alkyl; R4 is H, halo, trifluoromethyl, a C1-C8 unsubstituted alkyl or a substituted amino; R8f is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, halo and alkoxy; Q is substituted aryl or a substituted or unsubstituted heteroaryl and the bond indicates the presence of either an E or Z double bond configuration. In one variation of formula (X-1), R1 is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo or hydroxyl group. In one such variation, R1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (X-1), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH. In another variation of formula (X-1), R4 is H, halo, methyl, trifluoromethyl, or a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl). When R4 is a halo (e.g., fluoro or chloro), in one aspect R4 is chloro. In one variation of formula (X-1), R4 is H, methyl or chloro. In one variation of formula (X-1), R4 is methyl or chloro. When R4 is a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl), in one aspect C1-C8unsubstituted alkyl is a linear C1-C8unsubstituted alkyl such as methyl or ethyl. In a particular variation of formula (X-1), R4 is —N(H)(CH3). It is understood that any R1 for formula (X-1) may be combined with any R4 of formula (X-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (X-1) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH and R4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH3) Likewise, compounds of the formula (X-1) are provided where R1 is methyl and R4 is H, halo, methyl or a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl). In one such aspect, compounds of the formula (X-1) are provided where R1 is methyl and R4 is H, halo or methyl. In one such aspect, compounds of the formula (X-1) are provided where R1 is methyl and R4 is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. In one variation of formula (X-1), R8f is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R8f is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or an amido-substituted methyl group. In a particular variation, R8f is methyl. When Q of formula (X-1) is a substituted aryl, in one aspect Q is a substituted phenyl. In one aspect, Q is a mono-substituted phenyl. In a particular aspect, Q of formula (X-1) is a halo-substituted phenyl, alkoxy-substituted phenyl or an acylamino-substituted phenyl. Thus, compounds of the formula (X-1) are provided where Q in one variation is a phenyl mono-substituted with a fluoro, C1-C8 alkoxy (e.g., methoxy), an acylamino moiety of the formula —C(O)NH(C1-C8unsubstituted alkyl) or an acylamino moiety of the formula —C(O)N(C1-C8 unsubstituted alkyl)2, such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH3) and 4-(C(O)N(CH3)2)-phenyl. In one aspect, Q is a di-substituted phenyl. In one aspect, Q of formula (X-1) is a di-halo substituted phenyl group such as 3,4-difluoro-phenyl. In a particular aspect, Q of formula (C-1) is a phenyl group substituted with one halo group and one C1-C8 alkoxy group (e.g., methoxy). Thus, compounds of the formula (X-1) are provided where Q in one variation is a phenyl substituted with a fluoro and a C1-C8 alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When Q of formula (X-1) is a substituted or unsubstituted heteroaryl, in one variation the substituted or unsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (X-1), Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect of formula (X-1), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl. It is understood that any Q for formula (X-1) may be combined with any R1 and/or R4 of formula (X-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (X-1) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH; R4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH3) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (X-1) are provided where R1 is methyl; R4 is H, halo or methyl and Q is an unsubstituted pyridyl. In any variation of formula (X-1), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (X-1), in one aspect, the bond indicates the presence of a Z double bond configuration.
In specific variations, compounds of the formula (X-1) have the formula:




or a salt or solvate thereof; wherein R1, R4, R8f and Q are defined as for formula (X-1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (X-1) detailed throughout, where applicable, apply to formulae (X-1a) and (X-1b) the same as if each and every variation were specifically and individually listed for formulae (X-1a) and (X-1b). In one particular aspect of formula (X-1a), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH; R4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH3) R8f is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R1 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. In another aspect of formula (X-1a), R1 is methyl, R4 is H, chloro or methyl, R8f is methyl. and Q is a substituted or unsubstituted pyridyl. In one particular aspect of formula (X-1b), R1 is methyl, R4 is methyl, R8f is methyl. and Q is a substituted or unsubstituted pyridyl. Pharmaceutically acceptable salts of compounds of the formula (X-1), (X-1a) and (X-1b) are also provided.

In one variation, compounds of the formula (X-2) are provided:




or a salt or solvate thereof, where R1 is a substituted or unsubstituted C1-C8 alkyl; R4 is H, halo or a C1-C8 unsubstituted alkyl, R8f is substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted aryl, halo and alkoxy and the bond indicates the presence of either an E or Z double bond configuration and where R4 and the pyridyl moiety may be connected to the parent structure at any available position. In one variation of formula (X-2), R1 is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo or hydroxyl group. In one such variation, R1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (X-2), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH. In another variation of formula (X-2), R4 is H, halo, trifluoromethyl, or methyl. When R4 is a halo (e.g., fluoro or chloro), in one aspect R4 is chloro. In one variation of formula (X-2), R4 is H, methyl or chloro. In one variation of formula (X-2), R4 is methyl or chloro. In one variation of formula (X-1), R8f is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R1 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or an amido-substituted methyl group. In a particular variation, R8f is methyl. It is understood that any R1 for formula (X-2) may be combined with any R4 of formula (X-2) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (X-2) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH and R4 is H, chloro, fluoro, trifluoromethyl, or methyl. Likewise, compounds of the formula (X-2) are provided where R1 is methyl and R4 is H, halo or methyl. In one such aspect, compounds of the formula (X-2) are provided where R1 is methyl and R4 is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. In any variation of formula (X-2), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (X-2), in one aspect, the bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (X-2) have the formula:




or a salt or solvate thereof; wherein R1, R4 and R8f are defined as for formula (X-2). That is, variations of formula (X-2) detailed throughout, where applicable, apply to formulae (X-2a) and (X-2b) the same as if each and every variation were specifically and individually listed for formulae (X-2a) and (X-2b). Pharmaceutically acceptable salts of compounds of the formula (X-2), (X-2a) and (X-2b) are also provided.

Compounds of the formula (X-3) and (X-4) are also provided:




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; R4c is H, CH3, Cl, F, CF3, or —NHCH3; R9b is H or F; R9 is F, OCH3, —CONH(CH3) or —CON(CH3)2 and R8f is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one embodiment of formula (X-3) and (X-4), R1 is CH3; R4a is H; R4c is CH3, Cl, F or —NHCH3; R9b is H or F; R9 is F, OCH3, —CONH(CH3) or —CON(CH3)2; and R8f is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In a further embodiment, R1 is CH3; R4a is H; R4c is CH3, Cl, F or —NHCH3; R9b is H; R9c is F, OCH3; and R8f is methyl

Compounds of the formula (X-5) and (X-6) are also embraced,




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; R4c is H, CH3, Cl, F, CF3, or —NHCH3; and R8f is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In one embodiment of formula (X-5) and (X-6) R1 is CH3; R4a is H; R4c is CH3, Cl, F or —NHCH3; and R8f is CH3. In yet another variation, R1 is CH3; R4a is H; R4c is CH3, Cl or F; and R8f is CH3.

In one variation, compounds of the formula (X-7) or (X-8) are provided




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; R4c is H, CH3, Cl, F, CF3, or —NHCH3; R9c is H, F, CH3, CF3, OCH3, —CONH(CH3) or —CON(CH3)2; and R8f is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In one variation of formula (X-7) and (X-8) R1 is CH3; R4a is H; R4c is CH3, Cl, F, CF3, or —NHCH3; and R9c is H, F, CF3, or CH3; and R8f is methyl. In a particular variation, R1 is CH3; R4a is H; R4c is CH3, CF3, Cl or F; and R9c is H, CF3, or CH3.

In another variation, compounds of the formula (X-9) and (X-10) are provided:




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; and R4c is H, CH3, Cl, F, —CF3, or —NHCH3. R8f is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group In one embodiment of formula (X-9) and (X-10), R1 is CH3; R4a is H; and R4c is CH3, Cl, F, CF3, or —NHCH3. In one embodiment R1 is CH3; R4a is H; R4c is CH3, CF3, Cl or F; and R8f is methyl.

In one variation, compounds of the formula (C-1) are provided:




or a salt or solvate thereof, where R1, R4 and Q are defined as for formula (C) and, where applicable, any variation thereof detailed herein. That is, variations of formula (C) detailed throughout, where applicable, apply to formula (C-1) the same as if each and every variation were specifically and individually listed for formula (C-1).

In one variation, compounds of the formula (C-1) are provided, or a salt or solvate thereof, where R1 is a substituted or unsubstituted C1-C8 alkyl; R4 is H, halo, trifluoromethyl, a C1-C8 unsubstituted alkyl or a substituted amino; Q is substituted aryl or a substituted or unsubstituted heteroaryl and the bond indicates the presence of either an E or Z double bond configuration. In one variation of formula (C-1), R1 is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo or hydroxyl group. In one such variation, R1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (C-1), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH. In another variation of formula (C-1), R4 is H, halo, methyl, trifluoromethyl, or a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl). When R4 is a halo (e.g., fluoro or chloro), in one aspect R4 is chloro. In one variation of formula (C-1), R4 is H, methyl or chloro. In one variation of formula (C-1), R4 is methyl or chloro. When R4 is a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl), in one aspect C1-C8unsubstituted alkyl is a linear C1-C8unsubstituted alkyl such as methyl or ethyl. In a particular variation of formula (C-1), R4 is —N(H)(CH3). It is understood that any R1 for formula (C-1) may be combined with any R4 of formula (C-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (C-1) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH and R4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH3). Likewise, compounds of the formula (C-1) are provided where R1 is methyl and R4 is H, halo, methyl or a substituted amino of the formula —N(H)(C1-C8unsubstituted alkyl). In one such aspect, compounds of the formula (C-1) are provided where R1 is methyl and R4 is H, halo, trifluoromethyl, or methyl. In one such aspect, compounds of the formula (C-1) are provided where R1 is methyl and R4 is halo (e.g., fluoro or chloro) or methyl. When Q of formula (C-1) is a substituted aryl, in one aspect Q is a substituted phenyl. In one aspect, Q is a mono-substituted phenyl. In a particular aspect, Q of formula (C-1) is a halo-substituted phenyl, alkoxy-substituted phenyl or a acylamino-substituted phenyl. Thus, compounds of the formula (C-1) are provided where Q in one variation is a phenyl mono-substituted with a fluoro, C1-C8 alkoxy (e.g., methoxy), an acylamino moiety of the formula —C(O)NH(C1-C8 unsubstituted alkyl) or an acylamino moiety of the formula —C(O)N(C1-C8 unsubstituted alkyl)2, such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH3) and 4-(C(O)N(CH3)2)-phenyl. In one aspect, Q is a di-substituted phenyl. In one aspect, Q of formula (C-1) is a di-halo substituted phenyl group such as 3,4-difluoro-phenyl. In a particular aspect, Q of formula (C-1) is a phenyl group substituted with one halo group and one C1-C8 alkoxy group (e.g., methoxy). Thus, compounds of the formula (C-1) are provided where Q in one variation is a phenyl substituted with a fluoro and a C1-C8 alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When Q of formula (C-1) is a substituted or unsubstituted heteroaryl, in one variation the substituted or unsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (C-1), Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect of formula (C-1), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl. It is understood that any Q for formula (C-1) may be combined with any R1 and/or R4 of formula (C-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (C-1) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH; R4 is H, chloro, fluoro, trifluoromethyl, methyl or —N(H)(CH3) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (C-1) are provided where R1 is methyl; R4 is H, halo or methyl and Q is an unsubstituted pyridyl. In any variation of formula (C-1), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (C-1), in one aspect, the bond indicates the presence of a Z double bond configuration.
In specific variations, compounds of the formula (C-1) have the formula:




or a salt or solvate thereof; wherein R1, R4 and Q are defined as for formula (C-1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (C-1) detailed throughout, where applicable, apply to formulae (C-1a) and (C-1b) the same as if each and every variation were specifically and individually listed for formulae (C-1a) and (C-1b). In one particular aspect of formula (C-1a), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH; R4 is H, chloro, fluoro, methyl trifluoromethyl, or —N(H)(CH3) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. In another aspect of formula (C-1a), R1 is methyl, R4 is H, chloro or methyl and Q is a substituted or unsubstituted pyridyl. In one particular aspect of formula (C-1b), R1 is methyl, R4 is methyl and Q is a substituted or unsubstituted pyridyl. Pharmaceutically acceptable salts of compounds of the formula (C-1), (C-1a) and (C-1b) are also provided.

In one variation, compounds of the formula (C-2) are provided:




or a salt or solvate thereof, where R1 is a substituted or unsubstituted C1-C8 alkyl; R4 is H, halo or a C1-C8 unsubstituted alkyl and the bond indicates the presence of either an E or Z double bond configuration and where R4 and the pyridyl moiety may be connected to the parent structure at any available position. In one variation of formula (C-2), R1 is an unsubstituted C1-8 alkyl or a C1-C8 alkyl substituted with a halo or hydroxyl group. In one such variation, R1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (C-2), R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH. In another variation of formula (C-2), R4 is H, halo, trifluoromethyl, or methyl. When R4 is a halo (e.g., fluoro or chloro), in one aspect R4 is chloro. In one variation of formula (C-2), R4 is H, methyl or chloro. In one variation of formula (C-2), R4 is methyl or chloro. It is understood that any R1 for formula (C-2) may be combined with any R4 of formula (C-2) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (C-2) are provided where R1 is —CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH and R4 is H, chloro, fluoro, trifluoromethyl, or methyl. Likewise, compounds of the formula (C-2) are provided where R1 is methyl and R4 is H, halo or methyl. In one such aspect, compounds of the formula (C-2) are provided where R1 is methyl and R4 is halo (e.g., fluoro or chloro) or methyl. In any variation of formula (C-2), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (C-2), in one aspect, the bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (C-2) have the formula:




or a salt or solvate thereof; wherein R1 and R4 are defined as for formula (C-2). That is, variations of formula (C-2) detailed throughout, where applicable, apply to formulae (C-2a) and (C-2b) the same as if each and every variation were specifically and individually listed for formulae (C-2a) and (C-2b). Pharmaceutically acceptable salts of compounds of the formula (C-2), (C-2a) and (C-2b) are also provided.

Compounds of the formula (C-3a) and (C-3b) are also provided:




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; R4c is H, CH3, CF3, Cl, F or —NHCH3; R9b is H or F; and R9c is F, OCH3, —CONH(CH3) or —CON(CH3)2. In one embodiment of formula (C-3a) and (C-3b), R1 is CH3; R4a is H; R4c is CH3, Cl, F, CF3, or —NHCH3; R9b is H or F; and R9c is F, OCH3, —CONH(CH3) or —CON(CH3)2. In a further embodiment, R1 is CH3; R4a is H; R4c is CH3, Cl, F or —NHCH3; R9b is H; and R9c is F, OCH3.

Compounds of the formula (C-4a) and (C-4b) are also embraced,




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH) or —CH2CH2F; R4a is H or F; and R4c is H, CH3, Cl, F or —NHCH3. In one embodiment of formula (C-4a) and (C-4b), R1 is CH3; R4a is H and R4c is CH3, Cl, F, CF3, or —NHCH3. In yet another variation, R1 is CH3; R4a is H; R4c is CH3, CF3, Cl or F.

In one variation, compounds of the formula (C-5a) or (C-5b) are provided




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; R4c is H, CH3, Cl, F, CF3, or —NHCH3; and R9c is H, F, CH3, CF3, OCH3, —CONH(CH3) or —CON(CH3)2. In one variation of formula (C-5a) and (C-5b) R1 is CH3; R4a is H; R4c is CH3, Cl, F, CF3, or —NHCH3; and R9c is H, F, CF3, or CH3. In a particular variation, R1 is CH3; R4a is H; R4c is CH3, Cl or F; and R9c is H, CF3, or CH3.

In another variation, compounds of the formula (C-6a) and (C-6b) are provided:




or a salt or solvate thereof, wherein R1 is CH3, —CH2CH2—C(CH3)2(OH), —CH2CF3, or —CH2CH2F; R4a is H or F; and R4c is H, CH3, CF3, Cl, F or —NHCH3. In one embodiment of formula (C-6a) and (C-6b), R1 is CH3; R4a is H; and R4c is CH3, Cl, F, CF3, or —NHCH3. In one embodiment R1 is CH3; R4a is H; and R4c is CH3, CF3, Cl or F.

In one embodiment, the compound is of the formula (Ic) where R8c and R8e are taken together to form a bond and R8d and R8f are taken together to form a bond. In one embodiment, the compound is of the formula (D):




In one variation, the compound is of the formula (D), wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, compounds of the formula (D-1) are provided:




or a salt or solvate thereof; where R1, R4 and Q are as defined for formula (D). In one variation, Q of formula (D-1) is a substituted or unsubstituted aryl, such as phenyl. In one variation, R4 of formula (D-1) is halo, such as chloro. In one aspect, Q of formula (D-1) is a mono-substituted phenyl, such as a mono-halo substituted phenyl, for example 4-fluoro-phenyl. In another aspect, Q of formula (D-1) is a di-substituted phenyl, such as a 3,4-di-substituted phenyl, for example 3-fluoro-4-methoxyphenyl. In another variation Q of formula (D-1) is a di-substituted phenyl and R1 is an unsubstituted C1-C8 alkyl such as methyl. In another variation Q of formula (D-1) is a substituted phenyl and R4 is halo, such as chloro. In another variation Q of formula (D-1) is a di-substituted phenyl, R4 is halo such as chloro and R1 is an unsubstituted C1-C8 alkyl such as methyl.

The invention also embraces compound of the formula (Id):




where:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl;
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.
In one variation, the compound of the formula (Id) is provided, where each R1, R4, R10a, R10b, R11a, R11b, q and m are as defined for formula (Id); each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety; each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.
In one variation, the compound of the invention is of the formula (Id), where each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety. In another variation, the compound is of the formula (I), where each R2a, R2b, R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety and each R10a, R10b, R11a and R11b is independently H, substituted or unsubstituted C1-C8 alkyl or is taken together with the carbon to which it is attached to and a geminal R group to form a carbonyl moiety or a cycloalkyl moiety (e.g. cyclopropyl). In another variation, the compound is of the formula (Id), where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or a unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.
In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein where Q is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or a unsubstituted heterocyclyl, or a salt or solvate thereof. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein, where Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein, where Q is a heterocycle, such as a 5, 6 or 7 membered carbocycle.
In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein where Q is substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, or a salt or solvate thereof. In another variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein where Q is substituted or unsubstituted heteroaryl, such as a 5, 6 or 7 membered heteroaryl, or a salt or solvate thereof. In one variation, the compound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein where Q is a substituted or unsubstituted aryl, such as a 5, 6 or 7 membered aryl, or a salt or solvate thereof.
In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed herein where: R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; each R2a and R2b is independently H, methyl, fluoro or R2a and R2b are taken together to form a carbonyl moiety; each R3a and R3b is independently H or fluoro; each R10a and R10b is independently H, halo, hydroxyl or methyl or R10a and R10b are taken together to form a carbonyl, and each R11a and R11b is independently H or methyl or R11a and R11b are taken together to form a carbonyl. This variation is referred to as formula “Ie”. All variations referring to formula (I), where applicable, may apply equally to any of formula (Ia)-(Ie) the same as if each and every variation were specifically and individually listed.
In another variation, a compound of the invention is of the formula (I) or (Ie) where X7, X8, X9 and X10 are taken together to provide an aromatic moiety selected from the following structures:




where each R4 is as defined for formula (I) or (Ie); or in a particular variation, where each R4 is independently hydroxyl, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl; or in still a further variation, where R4 is independently halo, unsubstituted C1-C4 alkyl or C1-C4 perhaloalkyl. In another variation, each R4 is independently halo or an unsubstituted C1-C8 alkyl. In one embodiment, the foregoing rings are substituted with an (R4)1 substituent, such that that aromatic moiety is substituted is a single R4 group, which in one variation is halo or unsubstituted C1-C8 alkyl. In a particular variation, R4 is other than H. In one such variation, the foregoing rings have (R4)0 substituents, such that that aromatic moiety is unsubstituted and contains no R4 groups.

In another variation, compounds of any of the foregoing formulae are provided, where, if applicable, X7, X8, X9 and X10 are taken together to provide an aromatic moiety selected from the following structures:




where each R4 is as defined for the formulae; or in a particular variation, where each R4 is independently alkyl, perhaloalkyl or halo or in an even more particular variation, where each R4 is independently methyl, trifluoromethyl, chloro or fluoro. In one embodiment, the foregoing rings are substituted with an (R4)1 substituent, such that that aromatic moiety is substituted is a single R4 group, which in one variation is halo or unsubstituted C1-C8 alkyl. In a particular variation, R4 is other than H. In one such variation, the foregoing rings have (R4)0 substituents, such that that aromatic moiety is unsubstituted and contains no R4 groups.

In a further variation, compounds of any of the foregoing formulae are provided, where, if applicable, X7, X8, X9 and X10 are taken together to provide a structure of the following formulae, where R4 may be as defined in any variation hereinabove:




In one such variation, R4 is halo or an unsubstituted C1-C8 alkyl.

In a particular embodiment, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7, X8, X9 and X10 are CR4. In another embodiment, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where at least one of X7, X8, X9 and X10 is N. Another variation provides a compound of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where at least two of X7, X8, X9 and X10 are N. A further variation provides a compound of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where 2 of X7, X8, X9 and X10 are N and 2 of X7, X8, X9 and X10 are CR4. A compound of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where 1 of X7, X8, X9 and X10 is N and 3 of X7, X8, X9 and X10 are CR4 is also embraced by this invention.
In still a further variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7, X8, X9 and X10 are taken together to provide an aromatic moiety selected from the following structures:




wherein R4 is as defined in formula (I); or in a particular variation, where R4 is hydroxyl, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl; or in still a further variation, where each R4 is independently halo, unsubstituted C1-C4 alkyl or C1-C4 perhaloalkyl. In another variation, R4 is halo or unsubstituted C1-C8 alkyl. In yet another variation, compounds of any of the foregoing formulae are provided, where, if applicable, X7, X8, X9 and X10 are taken together to provide a structure of the formula:




In a particular variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7, X8, X9 and X10 are taken together to provide




In still a further variation, compounds of any of the foregoing formulae are provided, where, if applicable, X7, X8, X9 and X10 are taken together provide an aromatic moiety selected from the following structures:




wherein R4 is as defined in the formulae or in any particular variation herein, such as when each R4 is independently alkyl or halo or in an even more particular variation, where each R4 is independently methyl, chloro, iodo or fluoro.

In yet another variation, compounds of any of the foregoing formulae are provided, where, if applicable, X7, X8, X9 and X10 are taken together provide an aromatic moiety selected from the following structures:




In another embodiment, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, wherein X7-X10 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein or as detailed in any variation herein, where R1 is H, substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl. In a further embodiment, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, wherein X7-X10 are as defined in formula (I) or as detailed in any variation herein, where R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In a particular variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, wherein X7-X10 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.
In another variation, the compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R2a and R2b are independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or R2a and R2b are taken together to form a carbonyl moiety and each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano or nitro. In another variation, the compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R2a and R2b is independently H, unsubstituted C1-C8 alkyl, halo or R2a and R2b are taken together to form a carbonyl moiety and each R3a and R3b is independently H, unsubstituted C1-C8 alkyl, halo or R3a and R3b are taken together to form a carbonyl moiety. The invention also embraces compounds of the invention according to formula (I), where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R2a and R2b is independently H, methyl, halo or R2a and R2b are taken together to form a carbonyl moiety and each R3a and R3b is independently H, methyl, halo or R3a and R3b are taken together to form a carbonyl moiety. The invention further embraces compounds of the invention according to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each of R2a, R2b, R3a and R3b is H. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R2a, R2b, R3a and R3b is a substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least two of R2a, R2b, R3a and R3b is a substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R2a, R2b, R3a and R3b is fluoro or methyl or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a carbonyl moiety. In still another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where X7-X10 and R1 are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where either R2a and R2b or R3a and R3b are each methyl or fluoro (e.g., both R2a and R2b are methyl or one is fluoro and one is methyl) or are taken together to form a carbonyl moiety. In one variation, R2a and R2b are taken together to form a carbonyl moiety. In another variation, at least one of R2a and R2b is hydroxyl or alkoxy. In a particular variation, each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or R2a and R2b are taken together to form a carbonyl. In another variation, when X1 is N, each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro or R2a and R2b are taken together to form a carbonyl.
The invention also embraces compounds according to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R10a and R10b is independently H, halo, an unsubstituted C1-C8 alkyl, hydroxyl or R10a and R10b are taken together to form a cycloalkyl or a carbonyl. Also embraced are compounds according to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein or as detailed in any variation herein, where each R10a and R10b is independently H, halo, an unsubstituted C1-C4 alkyl, hydroxyl or R10a and R10b are taken together to form a cycloalkyl or a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R10a and R10b is independently H, bromo, methyl, hydroxyl or R10a and R10b are taken together to form a cyclopropyl or a carbonyl. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R10a and R10b is an unsubstituted C1-C8 alkyl, hydroxyl, halo or R10a and R10b are taken together to form a cycloalkyl or a carbonyl. In still a further variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R10a and R10b is methyl, bromo, hydroxyl or R10a and R10b are taken together to form a cyclopropyl or a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where both R10a and R10b are methyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R10a and R10b are taken together to form a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R10a is H and R10b is methyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R10a is H and R10b is bromo. When the carbon of formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein bearing R10a and R10b is optically active, it may be in the S or R configuration and compositions comprising substantially pure R or S compound or mixtures thereof in any amount are embraced by this invention.
The invention also embraces compounds according to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R11a and R11b is independently H, halo, an unsubstituted C1-C8 alkyl, hydroxyl or R11a and R11b are taken together to form a cycloalkyl or a carbonyl. Also embraced are compounds according to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein or as detailed in any variation herein, where each R11a and R11b is independently H, halo, an unsubstituted C1-C4 alkyl, hydroxyl or R11a and R11b are taken together to form a cycloalkyl or a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where each R11a and R11b is independently H, bromo, methyl, hydroxyl or R11a and R11b are taken together to form a cyclopropyl or a carbonyl. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R11a and R11b is an unsubstituted C1-C8 alkyl, hydroxyl, halo or R1la and R11b are taken together to form a cycloalkyl or a carbonyl. In still a further variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where at least one of R11a and R11b is methyl, bromo, hydroxyl or R11a and R11b are taken together to form a cyclopropyl or a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where both R11a and R11b are methyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R11a and R11b are taken together to form a carbonyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R11a is H and R11b is methyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where X7-X10, R1, R2a, R2b, R3a and R3b are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R11a is H and R11b is bromo. When the carbon of formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein bearing R11a and R11b is optically active, it may be in the S or R configuration and compositions comprising substantially pure R or S compound or mixtures thereof in any amount are embraced by this invention.
In a particular variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where R1, R2a, R2b, R3a, R3b, R10a, R10a, R10b, R11a and R11b are taken together to form a ring selected from the structures:




where R1 in the structures above is as defined for formula (I), (Ia), (Ib), (Ic) or (C) or any particular variation detailed herein.

Compounds of the formulae (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7) and (II-8) are also embraced by this invention:







where in each of (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7) and (II-8), R1, R2a, R2b, R3a, R3b, R10a, R10b, R11a, R11b, R8a-R8f, m, q and Q are as described for formula (I), (Ia), (Ib), (Ic) or (C) or any applicable variation thereof.

Compounds of the formulae (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12), (III-13), (III-14) and (III-15) are further embraced this invention:













where in each of formulae (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12), (III-13), (III-14) and (III-15), R1, R4, R2a, R2b, R3a, R3b, R10a, R10b, R11a, R11b, R8a-R8f, m, q and Q are as described for formula (I), (Ia), (Ib), (Ic) or (C) or any applicable variation thereof.

Compounds of the formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8) and (IV-9) are further embraced by this invention:










where in each of formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8) and (IV-9), R1, R4, R2a, R2b, R3a, R3b, R10a, R10b, R11a, R11b, R8a-R8f, m, q and Q are as described for formula (I), (Ia), (Ib), (Ic) or (C) or any applicable variation thereof.

The invention also embraces compounds of the formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15), (V-16), (V-17), (V-18), (V-19), (V-20), (V-21), (V-22), (V-23), (V-24), (V-25), (V-26) and (V-27) are also embraced by this invention:






















where in each of formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15), (V-16), (V-17), (V-18), (V-19), (V-20), (V-21), (V-22), (V-23), (V-24), (V-25), (V-26) and (V-27), R1, R4, R2a, R2b, R3a, R3b, R10a, R10b, R11a, R11b, R8a-R8f, m, q and Q are as described for formula (I), (Ia), (Ib), (Ic) or (C) or any applicable variation thereof.

The invention embraces a compound according to formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided: (i) at most one pair of vicinal R8 groups are taken together to form a bond; and (ii) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, unsubstituted C1-C4 alkyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with the carbon to which it is attached and a geminal R8 to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, methyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cyclopropyl moiety. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a geminal R8 to form a methylene (CH2═) or a substituted methylene such as CH3CH═ or the like. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 to form a bond, where the resultant double bond is in E- or Z-configuration. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 and the carbons to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 and the carbons to which they are attached to form a C3-C8 cycloalkyl. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or is of any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where R8c, R8d and the carbon to which they are attached are taken together with two other R8 groups that are geminal to each other and the carbon to which they are attached to form a C3-C8 cycloalkenyl. In yet another variation, a compound of the invention is of the formula (I), (Id) or (Ie) or any variation thereof detailed herein, or is any one of the formulae (II-1)-(II-8), (III-1)-(II-15), (IV-1)-(IV-9) or (V-1)-(V-27), where wherein q is 0 and m is 1. The invention also embraces a compound of the invention according to formula (I), (Id) or (Ie) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where q and m are both 0.
In certain embodiments, compounds of formulae detailed herein are provided where R1 is selected from the following moieties:




The invention further embraces a compound according to formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where q, m, R8a, R8b, R8c, R8d, R8e and R8f are taken together to form a moiety selected from the group consisting of the structures:




The invention further embraces a compound according to formula (A) or (A-1) or any variation thereof detailed herein, where q, m, R8a, R8b, R8c, R8d, R8g and R8h are taken together with the carbons to which they are attached to form a moiety selected from the group consisting of the structures:




The invention further embraces a compound according to formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where R8c, R8d and the carbon to which they are attached are taken together with R8e, R8f and the carbon to which they are attached or R8a, R8b and the carbon to which they are attached to form a moiety selected from the group consisting of the structures, each of which may be optionally substituted, where each R8 is independently H, hydroxyl, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy or carbonylalkoxy:




In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R4 is independently H, halo, substituted or unsubstituted C1-C8 alkyl, C1-C8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R4 is independently H or a substituted or unsubstituted C1-C8 alkyl. In still another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R4 is H. The invention also embraces compounds of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R4 is independently H, halo, unsubstituted C1-C4 alkyl, C1-C4 perhaloalkyl or a substituted or unsubstituted aryl. The invention further embraces compounds of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where each R4 is independently H, halo, methyl, trifluoromethyl or cyclopropyl.
The invention also embraces compounds of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, which may be but is not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstituted phenyl or pyridyl group. In a particular variation, Q is a phenyl or pyridyl group substituted with at least one methyl group. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C1-C8 alkyl, halo or perhaloalkyl moiety. In still another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclyl. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particular variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group. In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is an unsubstituted cycloalkyl or an unsubstituted heterocyclyl. In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein or (Ie) or any variation of the foregoing detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group.
In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) wherein each m and q is 0. In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) wherein each m and q is 1. In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) wherein m=1 and q=0.
In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or an unsubstituted heterocyclyl, or a salt or solvate thereof. In one variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. In one variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is a heterocycle, such as a 5, 6 or 7 membered carbocycle.
In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, or a salt or solvate thereof. In another variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is substituted or unsubstituted heteroaryl, such as a 5, 6 or 7 membered heteroaryl, or a salt or solvate thereof. In one variation, the compound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicable variation thereof, Q is a substituted or unsubstituted aryl, such as a 5, 6 or 7 membered aryl, or a salt or solvate thereof.
Q groups may be attached to the parent structure at any available position on the Q moiety. Thus, although specific attachment points for certain Q moieties are depicted herein, it is understood that such Q moieties, may also be connected to the parent structure at any available position. For example, if a 2-fluoro-phenyl is depicted herein, it is understood that other mono-fluoro-phenyls are intended, e.g., 3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that any formula detailed herein, where applicable, may in one variation have a Q moiety as detailed herein.
In still another variation, a compound of the invention is of the formulae or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R9 group. In another variation, Q is substituted with only one R9 group. In one variation, Q is substituted with two R9 groups. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R9)0 such that Q either contains no R9 functionality or a moiety of the formula N—R9.

In still another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R9 group. In another variation, Q is substituted with only one R9 group. In one variation, Q is substituted with two R9 groups. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R9)0-2 such that Q either contains no R9 functionality or a moiety of the formula N—R9.

In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




and wherein R9 is connected to Q ortho or para to the position at which Q is connected to the carbon bearing R8e and R8f. In a particular variation, Q is a structure of the formula:





and R9 is connected to Q para to the position at which Q is connected to the carbon bearing R8e and R8f. In another particular variation, Q is a structure of the formula





where each R9 is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:







wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R9 group. In another variation, Q is substituted with only one R9 group. In yet another variation, Q is substituted with two R9 groups. In a particular variation, Q is selected from the carbocyclic and heterocyclic structures detailed where the residue has the moiety (R9)0-2 such that Q either contains no R9 functionality or a moiety of the formula N—R9.

In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R9 group. In another variation, Q is substituted with only one R9 group. In yet another variation, Q is substituted with two R9 groups. In a particular variation, Q is selected from the carbocyclic and heterocyclic structures detailed where the residue has the moiety (R9)0-2 such that Q either contains no R9 functionality or a moiety of the formula N—R9.

In any structure or variation detailed herein containing an R9 group, in one variation, each R9 is independently a substituted or unsubstituted C1-C4 alkyl, halo, trifluoromethyl or hydroxyl. In another variation, each R9 is independently methyl, —CH2OH, isopropyl, halo, trifluoromethyl or hydroxyl.
In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:







In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In one variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:







In another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or a compound according to any one of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moiety selected from the structures:




In a further variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein where R1 is an unsubstituted alkyl, R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b are each H, each X7, X8, X9 and X10 is independently N or CH, each R8a, R8b, R8c, R8d, R8e and R8f is independently H or hydroxyl, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted phenyl or pyridyl group. Where Q is a substituted phenyl or pyridyl group, in one variation it is substituted with at least one methyl group.
In one variation, compounds of the formulae detailed herein are provided, such as compounds of the formulae (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, where R1 is selected from the following moieties:




In yet a further variation, a compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl; each R2a and R2b is independently H, unsubstituted C1-C8 alkyl or halo; each R3a and R3b is independently H or halo; each X7, X8, X9 and X10 is CR4, where R4 is as defined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein or in a particular variation, R4 is H, halo, pyridyl, methyl or trifluoromethyl; each R10a, R10b, R11a and R11b is independently H, unsubstituted C1-C8 alkyl, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In a particular variation, Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C1-C8 alkyl, halo or perhaloalkyl moiety. In one variation, a compound of the variation detailed herein is provided wherein R1 is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.
In still a further variation, a compound of the invention is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein where R1 is a substituted or unsubstituted C1-C8 alkyl; each R2a, R2b, R3a and R3b is independently H or halo; each R4 is independently H, halo, C1-C8 perhaloalkyl, substituted or a unsubstituted C1-C8 alkyl; each R8a, R8b, R8c, R8d, R8e and R8f is H; and Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. The invention also embraces a compound of the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where R1 is a methyl; at least one of X7, X8, X9 and X10 is CR4, and each R4 is independently H, halo, methyl or trifluoromethyl. The invention embraces compounds where Q in any variation detailed is substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group.
In a particular variation, the compound is of the formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein where R1 is a substituted or unsubstituted C1-C8 alkyl; each R2a, R2b, R3a and R3b is H; each R4 is independently H, halo or substituted or unsubstituted C1-C8 alkyl; each R8a, R8b, R8c, R8d, R8e and R8f is H; each R10a, R10b, R11a and R11b is independently H, unsubstituted C1-C8 alkyl, fluoro or R10a and R10b are taken together to form a carbonyl or R11a and R11b are taken together to form a carbonyl. In one aspect of this variation, Q may be a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In another aspect of this variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group. In another aspect of this variation, Q is a substituted amino, alkoxy or substituted alkoxy. In yet another aspect of this variation, X7, X8, X9 and X10 are CR4 and each R4 is independently H, halo or methyl.
Examples of compounds according to the invention are depicted in Table 2. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.







TABLE 2







Representative Compounds According to the Invention.










No.
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Additional compounds of the invention are provided by formulae (J-1)-(J-11) as detailed below
Compounds of the formula (J-1) are provided:




wherein:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each Z1, Z2, Z3 and Z4 is independently N or CR2;
each R2 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
X is H, OH, substituted or unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety;
Y is halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety; and
R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy, provided that when R3 is carbonylalkoxy, Y is halo, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety;
or a salt or solvate thereof.
In one variation, the salt of formula (J-1) is a pharmaceutically acceptable salt.
In one variation of formula (J-1), Z1, Z2, Z3 and Z4 are each CR2 and the compound is of the formula (J-2):




where R1, R2, R3, X and Y are as defined for formula (J-1). In one aspect of formula (J-2), at least one of the R2 moieties is H. In another aspect of formula (J-2), at least two R2 moieties are H. In a further aspect of formula (J-2), at least three R2 moieties are H, such as when (J-2) is of the formula (J-3):





In one variation of formula (J-3), R2 is halo or an unsubstituted C1-C8 alkyl, such as when R2 is chloro or methyl. In one aspect, compounds of the formula (J-3) are provided wherein the compound further has one or more of the following structural features: (i) R1 is a substituted or unsubstituted C1-C8 alkyl; (ii) R3 is an acylamino, carbonylalkoxy or aminoacyl moiety; (iii) X is H, OH, unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety, (iv) Y is halo, unsubstituted aryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety and (v) R2 is halo or an unsubstituted C1-C8 alkyl. In a particular variation, compounds of the formula (J-3) are provided wherein at least two of provisions (i)-(v) apply. In a particular variation, compounds of the formula (J-3) are provided wherein at least three of provisions (i)-(v) apply. In a particular variation of formula (J-3), X and Y are as defined in provisions (iii) and (iv). In a further such variation, X and Y are as defined in provisions (iii) and (iv) and at least one of provisions (i), (ii) and (v) also apply.

Compounds of the formula (J-1) where at least one of Z1, Z2, Z3 and Z4 is N are also embraced. In one aspect, Z1 is N. In another aspect, Z2 is N. In a further aspect, Z3 is N. In yet another aspect, Z4 is N. Where more than one of Z1, Z2, Z3 and Z4 is N, the N atoms may be positioned at any available annular ring position. For example, when Z1 is N, any of Z2, Z3 or Z4 may also be N.
In another variation of formula (J-1), (J-2) or (J-3), R1 is a substituted or unsubstituted C1-C8 alkyl. In a further variation of formula (J-1), (J-2) or (J-3), R1 is an unsubstituted C1-C4 alkyl such as methyl.
In still a further variation of formula (J-1), (J-2) or (J-3), R3 is an acylamino, carbonylalkoxy or aminoacyl moiety. In one aspect of formula (J-1), (J-2) or (J-3), when R3 is an acylamino moiety, R3 is an acyclic acylamino moiety, such as when R3 is an acyclic acylamino moiety of the formula —C(O)NRaRb where Ra is H or a C1-C8 substituted or unsubstituted alkyl and Rb is H, a C1-C8 substituted or unsubstituted alkyl (e.g., methyl, ethyl, isopropyl or benzyl) or a heterocycle. In another aspect of formula (J-1), (J-2) or (J-3), when R3 is an acylamino moiety, R3 is an acyclic acylamino moiety, such as when R3 is of the formula —C(O)NRaRb where Ra taken together with Rb and the nitrogen to which they are attached to form a 3-8 membered heterocyclic ring (e.g., —C(O)(1-piperidinyl). In one aspect of formula (J-1), (J-2) or (J-3), when R3 is a carbonylalkoxy moiety, R3 is of the formula —C(O)O-alkyl (e.g., methyl, ethyl, cyclopentyl) or —C(O)O-substituted alkyl and Y is halo, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety. For instance, in one variation of formula (J-1), (J-2) or (J-3), R3 is a carbonylalkoxy moiety of the formula —C(O)OR where R is a C1-C8 substituted or unsubstituted alkyl, where in one variation the substitute on the C1-C8 substituted alkyl is one or more halo groups, such as an alkyl substituted with a perhaloalkyl moiety. Compounds of the formula (J-1), (J-2) or (J-3) are provided where R3 is an aminoacyl moiety of the formula —NRaC(O)Rb where Ra is H and Rb is an unsubstituted or substituted alkyl, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or a substituted or unsubstituted heterocyclic moiety. In one aspect of formula (J-1), (J-2) or (J-3), R3 is an aminoacyl moiety of the formula —NRaC(O)Rb where Ra is H and Rb is a C1-C8 unsubstituted or substituted alkyl; in another such aspect, Ra is H and Rb is an unsubstituted C1-C4 alkyl. In another aspect of formula (J-1), (J-2) or (J-3), R3 is an aminoacyl moiety of the formula —NRaC(O)Rb where Ra is H and Rb is an unsubstituted or substituted single ring aryl moiety, an unsubstituted or substituted single ring heteroaryl moiety, or a substituted or unsubstituted single ring heterocyclic moiety, where the heteroaryl or heterocyclic moieties in one variation bear nitrogen heteroatoms (e.g., pyridinyl, piperidinyl).
Compounds of the formula (J-1), (J-2) or (J-3) are also provided where X is H, OH, unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety, and Y is halo, unsubstituted aryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety. In one variation of formula (J-1), (J-2) or (J-3), X is H, OH or an unsubstituted C1-C8 alkyl (e.g., methyl) and Y is halo, an unsubstituted C1-C8 alkyl (e.g., methyl, isopropyl, n-butyl or cyclobutyl) or an unsubstituted single ring aryl moiety (e.g., phenyl). In one variation of formula (J-1), (J-2) or (J-3), X is OH and Y is an unsubstituted aryl. In one aspect, Y is phenyl. In another variation, X is H and Y is a C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety. In one aspect, Y is a methylene substituted with a carbonylalkoxy, carboxyl or acylamino moiety. In a particular aspect, Y is a moiety selected from the following structures




where each R4 and R5 is independently an unsubstituted C1-C8 alkyl. In one variation, Y is a moiety selected from the following structures





where each R4 and R5 is independently an unsubstituted C1-C8 alkyl and X is H. In another variation, X is an unsubstituted C1-C8 alkyl and Y is halo. In a particular aspect, Y is fluoro.

In a particular variation of formula (J-1), (J-2) or (J-3), R1 is an unsubstituted C1-C4 alkyl; X is H, OH, unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety; Y is halo, unsubstituted aryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety; and R3 is an acylamino, carbonylalkoxy or aminoacyl moiety, provided that when R3 is carbonylalkoxy, Y is halo, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety. In another variation of formula (J-1), (J-2) or (J-3), R1 is an unsubstituted C1-C4 alkyl; X is H, OH, unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety; Y is halo, unsubstituted aryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety; and R3 is an acylamino or aminoacyl moiety. It is understood that when R3 is an acylamino, carbonylalkoxy or aminoacyl moiety, R3 may be any such moiety detailed herein, including but not limited to the moieties provided herein above. As such, it is understood that in one aspect, compounds of the formula (J-1), (J-2) or (J-3) are provided wherein R1 is an unsubstituted C1-C4 alkyl; X is H, OH, unsubstituted C1-C8 alkyl or is taken together with Y to form a moiety of the formula —OCH2CH2O—, or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety; Y is halo, unsubstituted aryl, unsubstituted C1-C8 alkyl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with X to form a moiety of the formula —OCH2CH2O—, or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety; and R3 is an acyclic or cyclic acylamino as detailed herein or an aminoacyl moiety of the formula —NRaC(O)Rb where Ra is H and Rb is an unsubstituted or substituted alkyl, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or a substituted or unsubstituted heterocyclic moiety.
In one variation of formula (J-3), R1 is unsubstituted C1-C8 alkyl or a C1-C8 alkyl substituted with a perhaloalkyl moiety; and R2 is independently H, halo, unsubstituted C1-C8 alkyl or unsubstituted C1-C8 alkoxy. In one variation of formula (J-3), R1 is unsubstituted C1-C8 alkyl; R2 is unsubstituted C1-C8 alkyl, H or halo, and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.
In one variation of formula (J-3), X is OH and Y is a substituted or unsubstituted C1-C8 alkyl. In another variation of (J-3), X is OH and the compound is further defined by one or more of the following structural features: (i) Y is a substituted or unsubstituted C1-C8 alkyl (which in one aspect is methyl, butyl or isopropyl); (ii) R1 and R2 are independently an unsubstituted C1-C8 alkyl (in one aspect both R1 and R2 are methyl); (iii) R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation of formula (J-3), X is OH, Y is a substituted or unsubstituted C1-C8 alkyl; R1 and R2 are each methyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.
In one variation of formula (J-3), X is OH and Y is H. In one variation of formula (J-3), X is OH; Y is H; and R1 and R2 are independently an unsubstituted C1-C8 alkyl. In a particular variation of formula (J-3), X is OH; Y is H; R1 and R2 are independently an unsubstituted C1-C8 alkyl; and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In one variation of formula (J-3), X is OH; Y and H; R1 and R2 are each methyl; and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation of formula (J-3), X is OH; Y is H; R1 and R2 are each methyl; and R3 is acylamino, carbonylalkoxy or aminoacyl.
Compounds of the formula (J-4) are detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (J-1). In one variation of formula (J-4), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In a particular variation of formula v, R1 and R2 are independently an unsubstituted C1-C8 alkyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In one variation, R1 and R2 are each methyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In another variation of formula (J-4), R1 is an unsubstituted C1-C8 alkyl; R2 is halo or an unsubstituted C1-C8 alkyl and R3 is aminoacyl. In one such variation of formula (J-4), R1 is methyl; R2 is halo or a C1-C4 unsubstituted alkyl; and R3 is an aminoacyl of the formula —NRaC(O)Rb where Ra is H and Rb is an unsubstituted or substituted alkyl, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or a substituted or unsubstituted heterocyclic moiety.

Compounds of the formula (J-5) are also detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (J-1). In one variation of formula (J-5), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl). In another variation of formula (J-5), R2 is H, an unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In one aspect of formula (J-5), R1 is an unsubstituted C1-C8 alkyl and R2 is H, an unsubstituted C1-C8 alkyl or halo. In another variation of formula (J-5), R2 is a halo or an unsubstituted C1-C8 alkyl and R1 is an unsubstituted C1-C4 alkyl. In a particular variation of formula (J-5), R1 is methyl and R2 is H, methyl or chloro. In one variation of formula (J-5), R1 and R2 are independently an unsubstituted C1-C8 alkyl such as methyl. In a further variation of formula (J-5), R1 is an unsubstituted C1-C8 alkyl; R2 is H, an unsubstituted C1-C8 alkyl or halo and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation, compounds of formula (J-5) are provided where R1 is methyl, R2 is H, methyl or chloro and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a further variation of formula (J-5), R1 is an unsubstituted C1-C8 alkyl; R2 is halo or an unsubstituted C1-C8 alkyl; and R3 is an acylamino of the formula —C(O)NRaRb where Ra is H and Rb is an unsubstituted C1-C8 alkyl.

Compounds of the formula (J-6) are also detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as detailed for formula (J-1) and R4 is an unsubstituted C1-C8 alkyl. In one variation of formula (J-6), R1 is an unsubstituted C1-C8 alkyl. In one variation of formula (J-6), R2 is an unsubstituted C1-C8 alkyl or halo. In one variation of formula (J-6), R1 and R2 are independently an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl). In one variation of formula (J-6), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl) and R2 is an unsubstituted C1-C8 alkyl or halo. In a particular variation of formula (J-6), R4 is an unsubstituted C1-C4 alkyl. In a further variation of formula (J-6), R4 is methyl, ethyl, propyl or butyl. In one aspect, R4 is iso-propyl. In another aspect, R4 is tert-butyl. In a particular variation of formula (J-6), R1 is an unsubstituted C1-C8 alkyl; R2 is an unsubstituted C1-C8 alkyl or halo and R4 is an unsubstituted C1-C4 alkyl. In a further variation of formula (J-6), R1 is an unsubstituted C1-C8 alkyl; R2 is an unsubstituted C1-C8 alkyl or halo; R4 is an unsubstituted C1-C4 alkyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation, compounds of formula (J-6) are provided where R1 is methyl or ethyl, R2 is methyl or chloro; R4 is methyl, ethyl, isopropyl or tert-butyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a further variation of formula (J-6), R1 is an unsubstituted C1-C4 alkyl; R2 is an unsubstituted C1-C4 alkyl or halo; R4 is an unsubstituted C1-C4 alkyl; and R3 is acylamino or aminoacyl. In yet a further variation of formula (J-6), R1 is an unsubstituted C1-C4 alkyl; R2 is an unsubstituted C1-C4 alkyl or halo; R4 is an unsubstituted C1-C4 alkyl; and R3 is either an acylamino of the formula —C(O)NRaRb where Ra and Rb are independently an unsubstituted C1-C8 alkyl or Ra and Rb are taken together with the nitrogen to which they are attached to form a heterocyclic moiety or an aminoacyl.

Compounds of the formula (J-7) are also detailed herein:




or a salt of solvate thereof, where R1, R2 and R3 are as detailed for formula (J-1). In one variation of formula (J-7), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl). In another variation of formula (J-7), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (J-7), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (J-7), R1 and R2 are independently an unsubstituted C1-C8 alkyl (e.g., methyl). In one variation of formula (J-7), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation of formula (J-7), R1 and R2 are independently an unsubstituted C1-C8 alkyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In one variation of formula (J-7), R3 is acylamino.

Compounds of the formula (J-8) are also detailed herein:




or a salt of solvate thereof, where R1, R2 and R3 are as detailed for formula (J-1) and R5 is an unsubstituted C1-C8 alkyl. In one variation of formula (J-8), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl). In another variation of formula (J-8), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (J-8), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (J-8), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In a particular variation of formula (J-8), R5 is an unsubstituted C1-C4 alkyl. In a further variation of formula (J-8), R5 is methyl, ethyl, propyl or butyl. In one aspect, R5 is iso-propyl. In another aspect, R5 is tert-butyl. In one variation of formula (J-8), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a further variation of formula (J-8), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is acylamino, or aminoacyl.

Compounds of the formula (J-9) are also detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (J-1) and R6 is an unsubstituted C1-C8 alkyl. In one variation of formula (J-9), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl, ethyl or isopropyl). In another variation of formula (J-9), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (J-9), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (J-9), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In a particular variation of formula (J-9), R6 is an unsubstituted C1-C4 alkyl. In a further variation of formula (J-9), R6 is methyl, ethyl, propyl or butyl. In one aspect, R6 is iso-propyl. In another aspect, R6 is tert-butyl. In one variation of formula (J-9), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.

Compounds of the formula (J-10) are also detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (J-1). In one variation of formula (J-10), R1 and R2 are each an unsubstituted C1-C8 alkyl group. In another variation of formula (J-10), R1 and R2 are each an unsubstituted C1-C8 alkyl group and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In another variation of formula (J-10), R1 is an unsubstituted C1-C8 alkyl; R2 is an unsubstituted C1-C8 alkyl or halo and R3 is acylamino or aminoacyl.
Compounds of the formula (J-11) are also detailed herein:




wherein:

each Z1, Z2, Z3 and Z4 is independently N or CR2 
each R2 is independently H, halo, unsubstituted C1-C8 alkyl or unsubstituted C1-C8 alkoxy;
R1 is unsubstituted C1-C8 alkyl or a C1-C8 alkyl substituted with a perhaloalkyl moiety;
X is OH, substituted or unsubstituted C1-C8 alkyl or is taken together with Y and the carbon to which they are attached to form a cyclopropyl moiety;
Y is H, substituted or unsubstituted C1-C8 alkyl or is taken together with X and the carbon to which they are attached to form a cyclopropyl moiety; and
R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy;
or a salt or solvate thereof.
In one variation, the salt of formula (J-11) is a pharmaceutically acceptable salt.
In one variation of formula (J-11), each of Z1, Z2, Z3 and Z4 is CR2. In another variation of formula (J-11), at least one of Z1, Z2, Z3 and Z4 is N, which may positioned at any of Z1, Z2, Z3 and Z4. Where more than one of Z1, Z2, Z3 and Z4 is N, the annular nitrogen atoms may be located at any available positions.
In one variation of formula (J-11), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In a particular variation of formula (J-11), R1 and R2 are independently an unsubstituted C1-C8 alkyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In one variation, R1 and R2 are each methyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation of formula (J-11), R1 and R2 are each methyl and R3 is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.
Examples of compounds according to the invention are depicted in Table 2A. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.







TABLE 2A







Representative Compounds








Compound
Structure





J-1






 


J-2






 


J-3






 


J-4






 


J-5






 


J-6






 


J-7






 


J-8






 


J-9






 


J-10






 


J-11






 


J-12






 


J-13






 


J-14






 


J-15






 


J-16






 


J-17






 


J-18






 


J-19






 


J-20






 


J-21






 


J-22






 


J-23






 


J-24






 


J-25






 


J-26






 


J-27






 


J-28






 


J-29






 


J-30













Compounds of the formula (K-1) are also detailed herein:




wherein:

R1, R2, R3 and R4 are independently H, halo, C1-C8 unsubstituted alkyl or C1-C8 unsubstituted alkoxy, provided that R3 is other than methyl or chloro when R1, R2 and R3 are each H and X is OH and Y is methyl;
R5 is unsubstituted C1-C8 alkyl or a C1-C8 alkyl substituted with a perhaloalkyl moiety;
R6 is H or an unsubstituted C1-C8 alkyl;
X is OH, C1-C8 alkyl or is taken together with Y to form a cyclopropyl moiety;
Y is H, C1-C8 alkyl or is taken together with X to form a cyclopropyl moiety,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-1), R1 is H, halo or C1-C8 unsubstituted alkoxy; R2 is H; R3 is H, halo, C1-C8 unsubstituted alkyl or C1-C8 unsubstituted alkoxy, provided that R3 is other than methyl or chloro when R1, R2 and R3 are each H and X is OH and Y is methyl; R4 is H or halo; R5 is methyl; R6 is H or methyl; X is OH, C1-C8 alkyl or is taken together with Y to form a cyclopropyl moiety and Y is H, C1-C8 alkyl or is taken together with X to form a cyclopropyl moiety. In another variation of formula (K-1), at least two of R1, R2, R3 and R4 are halo (e.g., when R2 and R3 are chloro). In another variation of formula (K-1), X is OH and Y is H, methyl, ethyl or isopropyl. In a further variation of formula (K-1), R1, R2 and R4 are H. In another variation of formula (K-1), three of R1, R2, R3 and R4 are H and one is methyl, methoxy, isopropyl, chloro or fluoro.
Also provided are compounds of the formula (K-2):




wherein:

R7 is H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; and
Z is H, halo or C1-C8 alkyl,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-2), R7 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (K-2), Z is H or halo. In a further variation of formula (K-2), R7 is an unsubstituted C1-C8 alkyl or halo and Z is H or halo. In a particular variation, R7 is methyl or chloro and Z is H, chloro or fluoro.
Compounds of the formula (K-3) are also embraced:




wherein:

R1, R2, R3 and R4 are as defined for formula (K-1);
R8 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and
X is a C4-C6 unsubstituted n-alkyl or cycloalkyl or a C3-C6 unsubstituted branched alkyl,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-3), R1, R2 and R4 are each H and R3 is an unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In another variation of formula (K-3), X is cyclohexyl, cyclobutyl, n-butyl or iso-propyl. In a particular variation of formula (K-3), R1, R2 and R4 are each H; R3 is an unsubstituted C1-C8 alkyl or halo and X is cyclohexyl, cyclobutyl, n-butyl or iso-propyl. In a further variation of formula (K-3), R8 is a substituted aryl or an unsubstituted heteroaryl. In one aspect, R8 of formula (K-3) is a substituted phenyl or an unsubstituted pyridyl. In a particular aspect, R8 of formula (K-3) is 4-halo-phenyl or 4-pyridyl. In another variation of formula (K-3), R1, R2 and R4 are each H; R3 is an unsubstituted C1-C8 alkyl or halo; X is cyclohexyl, cyclobutyl, n-butyl and R8 is a substituted phenyl. In another variation of formula (K-3), R1, R2 and R4 are each H; R3 is an unsubstituted C1-C8 alkyl or halo; X is isopropyl and R8 is an unsubstituted pyridyl.
Compounds of the formula (K-4) are also provided:




wherein:

R1, R2, R3 and R4 are as defined for formula (K-1); and
V is a halo,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-4), R1, R2 and R4 are H and R3 is unsubstituted C1-C8 alkyl such as methyl. In another variation of formula (K-4), V is fluoro.
Compounds of the formula (K-5) are also detailed herein:




wherein:

R1, R2 and R4 are as defined for formula (K-1); and
R8 is 6-pyrimidyl, 3-methyl-4-pyridyl or a phenyl substituted either: (i) with at least one alkoxy or hydroxyl group or (ii) with at least two halo groups;
R9 is an unsubstituted C1-C3 alkyl;
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-5), R1, R2 and R4 are each H. In another variation of formula (K-5), R9 is methyl. In a further variation of formula (K-5), R1, R2 and R4 are each H and R9 is methyl. In another variation of formula (K-5), R8 is a phenyl substituted with at least one unsubstituted C1-C8 alkoxy group such as methoxy. In one aspect of formula (K-5), R1, R2 and R4 are each H and R8 is a methoxy-substituted phenyl. In another aspect of formula (K-5), R9 is methyl and R8 is a methoxy or hydroxyl-substituted phenyl. In another variation, R8 is a phenyl substituted with at least two halo groups and R1, R2 and R4 are each H.
Also provided are compounds of the formula (K-6):




wherein:

R1, R2, R3 and R4 are as defined for formula (K-1);
R5 is




where T is 3 or 4;

X is H or OH;
Y is H or C1-C8 alkyl; and
R8 is a substituted or unsubstituted heteroaryl,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one variation of formula (K-6), R1, R2 and R4 are H. In another variation of formula (K-6), R3 is unsubstituted C1-C8 alkyl. In another variation of formula (K-6), R1, R2 and R4 are H and R3 is unsubstituted C1-C8 alkyl. In another variation of formula (K-6), R8 is a substituted or unsubstituted pyridyl. When R8 is an unsubstituted pyridyl, it may be bound to the parent structure at any available position, e.g., 4-pyridyl. When R8 is a substituted pyridyl, in one aspect the pyridyl is substituted with an unsubstituted C1-C8 alkyl such as methyl. When R8 is a substituted pyridyl, it may be bound to the parent structure at any available ring position, e.g., 6-methyl-3-pyridyl. In a particular variation of formula (K-6), R1, R2 and R4 are H; R3 is unsubstituted C1-C8 alkyl and R8 is a substituted or unsubstituted pyridyl. In a further variation of formula (K-6), X and Y are both H. For example, in one aspect a compound is of the formula (K-6) where R1, R2 and R4 are H; R3 is unsubstituted C1-C8 alkyl and R8 is a substituted or unsubstituted pyridyl and X and Y are both H.
Compounds of the formula (K-7) are also detailed herein:




wherein:

R1, R2 and R4 are as defined for formula (K-1);
R3 is methyl or chloro, provided that R3 is methyl when R8 is a substituted heteroaryl;
X is H or OH;
Y is H or C1-C8 alkyl; and
R8 is a substituted or unsubstituted heteroaryl,
or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing.
In one aspect of formula (K-7), R1, R2 and R4 are each H. In another aspect of formula (K-7), X is H and Y is an unsubstituted C1-C8 alkyl. In another aspect of formula (K-7), Y and Y are both H. In a particular variation of formula (K-7), R1, R2 and R4 are each H and either (i) X and Y are both H or (ii) X is H and Y is an unsubstituted C1-C8 alkyl such as methyl. In a particular variation, R8 is a substituted or unsubstituted pyridyl. In a specific variation of formula (K-7), R8 is a substituted or unsubstituted pyridyl and either (i) X and Y are both H or (ii) X is H and Y is an unsubstituted C1-C8 alkyl.
Examples of compounds according to the invention are depicted in Table 2B. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.







TABEL 2B







Representative Compounds According to the Invention.








Compound
Structure





K-1






 


K-2






 


K-3






 


K-4






 


K-5






 


K-6






 


K-7






 


K-8






 


K-9






 


K-10






 


K-11






 


K-12






 


K-13






 


K-14






 


K-15






 


K-16






 


K-17






 


K-18






 


K-19






 


K-20






 


K-21






 


K-22






 


K-23






 


K-24






 


K-25






 


K-26






 


K-27






 


K-28






 


K-29






 


K-30






 


K-31






 


K-32






 


K-33






 


K-34






 


K-35






 


K-36






 


K-37






 


K-38






 


K-39






 


K-40






 


K-41






 


K-42






 


K-43






 


K-44






 


K-45






 


K-46






 


K-47






 


K-48






 


K-49






 


K-50






 


K-51






 


K-52






 


K-53






 


K-54






 


K-55






 


K-56






 


K-57






 


K-58






 


K-59













Compounds of the formula (L-1) are also provided:




wherein:

R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
R2 is H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
X is OH, H, C1-C8 unsubstituted alkyl or is taken together with Y to form a cyclic moiety of the formula —OCH2CH2O—;
Y is halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety or is taken together with X to form a cyclic moiety of the formula —OCH2CH2O—; and
R3 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl;
or a salt or solvate thereof.
In one variation of formula (L-1), R1 is C1-C8 unsubstituted alkyl; R2 is C1-C8 unsubstituted alkyl, H or halo and R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. In a particular variation of formula (L-1), R1 is methyl, ethyl or isopropyl; R2 is methyl, H or chloro and R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. When R3 is an unsubstituted aryl in one variation it is a phenyl moiety. When R3 is a substituted aryl in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a disubstituted phenyl substituent with two halo groups which may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. When R3 is an unsubstituted heteroaryl in one variation it is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation, R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation, R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, on one variation, R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation, R3 is 2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl.
In one variation of formula (L-1), X is OH and Y is an unsubstituted aryl. In one aspect, Y is phenyl. In another variation, X is H and Y is a C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety. In one aspect, Y is a methylene substituted with a carbonylalkoxy, carboxyl or acylamino moiety. In a particular aspect, Y is a moiety selected from the following structures




where R4 is a C1-C8 unsubstituted alkyl. In one variation, Y is a moiety selected from the following structures





where R4 is a C1-C8 unsubstituted alkyl and X is H. In another variation, X is an unsubstituted C1-C8 alkyl and Y is halo. In a particular aspect, Y is fluoro.

The invention also embraces compounds of the formula (L-2):




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (L-1). In one variation of formula (L-2), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In another variation of formula (L-2), R3 is a substituted aryl, such as a substituted phenyl group, or an unsubstituted heteroaryl, such as pyridyl. In one aspect, R3 is a halo substituted phenyl or pyridyl moiety. When R3 is a halo substituted phenyl, in a particular variation the phenyl is substituted with a fluoro that may be at any position on the phenyl ring. When R3 is a pyridyl group it may be bound to the parent structure at any available ring position. In a particular aspect, R3 is 4-pyridyl. In a particular variation of formula (L-2), R1 and R2 are independently an unsubstituted C1-C8 alkyl and R3 is a substituted aryl or an unsubstituted heteroaryl. In one variation, R1 and R2 are each methyl and R3 is a substituted aryl or unsubstituted heteroaryl. In a particular variation of formula (L-2), R1 and R2 are each methyl and R3 is a fluoro substituted phenyl or pyridyl moiety.

The invention also embraces compounds of the formula (L-3):




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (L-1). In one variation of formula (L-3), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl). In another variation of formula (L-3), R2 is H, an unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In one aspect of formula (L-3), R1 is an unsubstituted C1-C8 alkyl and R2 is H, an unsubstituted C1-C8 alkyl or halo. In a particular variation of formula (L-3), R1 is methyl and R2 is H, methyl or chloro. In one variation of formula (L-3), R1 and R2 are independently an unsubstituted C1-C8 alkyl such as methyl. In one variation of formula (L-3), R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, such as those listed herein for formula (L-1). For example, compounds of the formula (L-3) are intended wherein R3 is an unsubstituted aryl, which in one variation is a phenyl moiety. Compounds of the formula (L-3) are also intended wherein R3 is a substituted aryl, which in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a disubstituted phenyl substituent with two halo groups which may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds of formula (L-3) are provided where R3 is an unsubstituted heteroaryl, which in one variation is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation of formula (L-3), R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-3), R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-3), R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation of formula (L-3), R3 is 2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In another variation of formula (L-3), R3 is a substituted aryl, such as a substituted phenyl group. In one aspect, R3 is a halo substituted phenyl. When R3 is a halo substituted phenyl, in a particular variation the phenyl is substituted with a fluoro or chloro that may be at any position on the phenyl ring. In a further variation of formula (L-3), R1 is an unsubstituted C1-C8 alkyl; R2 is H, an unsubstituted C1-C8 alkyl or halo and R3 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl. In a particular variation, compounds of formula (L-3) are provided where R1 is methyl, R2 is H, methyl or chloro and R3 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (L-4) are also provided:




or a salt or solvate thereof, where R1, R2 and R3 are as detailed for formula (L-1) and R4 is an unsubstituted C1-C8 alkyl. In one variation of formula (L-4), R1 is an unsubstituted C1-C8 alkyl. In one variation of formula (L-4), R2 is an unsubstituted C1-C8 alkyl or halo. In one variation of formula (L-4), R1 and R2 are independently an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl). In one variation of formula (L-4), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl) and R2 is an unsubstituted C1-C8 alkyl or halo. In a particular variation of formula (L-4), R4 is a C1-C4 unsubstituted alkyl. In a further variation of formula (L-4), R4 is methyl, ethyl, propyl or butyl. In one aspect, R4 is iso-propyl. In another aspect, R4 is tert-butyl. In a particular variation of formula (L-4), R1 is an unsubstituted C1-C8 alkyl; R2 is an unsubstituted C1-C8 alkyl or halo and R4 is a C1-C4 unsubstituted alkyl. In another variation of formula (L-4), R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, such as those listed herein for formula (L-1). For example, compounds of the formula (L-4) are intended wherein R3 is a substituted aryl, which in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a dihalosubstituted phenyl wherein the halo moieties may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl or 4-methoxyphenyl. Compounds of formula (L-4) are also provided where R3 is an unsubstituted heteroaryl, which in one variation is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation of formula (L-4), R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-4), R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-4), R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation of formula (L-4), R3 is 2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In a further variation of formula (L-4), R1 is an unsubstituted C1-C8 alkyl; R2 is an unsubstituted C1-C8 alkyl or halo; R4 is a C1-C4 unsubstituted alkyl and R3 is a substituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl. In a particular variation, compounds of formula (L-4) are provided where R1 is methyl or ethyl, R2 is methyl or chloro; R4 is methyl, ethyl, isopropyl or tert-butyl and R3 is a substituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Also provided herein are compounds of the formula (L-5):




or a salt of solvate thereof, where R1, R2 and R3 are as detailed for formula (L-1). In one variation of formula (L-5), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl). In another variation of formula (L-5), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (L-5), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (L-5), R1 and R2 are independently an unsubstituted C1-C8 alkyl (e.g., methyl). In one variation of formula (L-5), R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, such as those listed herein for formula (L-1). For example, compounds of the formula (L-5) are intended wherein R3 is a substituted aryl, which in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a disubstituted phenyl substituent with two halo groups which may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds of formula (L-5) are also provided where R3 is an unsubstituted heteroaryl, which in one variation is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation of formula (L-5), R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-5), R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-5), R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation of formula (L-5), R3 is 2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula (L-5), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is a substituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl. In a particular variation of formula (L-5), R1 and R2 are independently an unsubstituted C1-C8 alkyl and R3 is a substituted phenyl, a substituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Additional compounds detailed herein are of the formula (L-6):




or a salt of solvate thereof, where R1, R2 and R3 are as detailed for formula (L-1). In one variation of formula (L-6), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl or ethyl). In another variation of formula (L-6), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (L-6), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (L-6), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In one variation of formula (L-6), R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, such as those listed herein for formula (L-1). For example, compounds of the formula (L-6) are intended wherein R3 is a substituted aryl, which in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a disubstituted phenyl substituent with two halo groups which may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds of formula (L-6) are also provided where R3 is an unsubstituted heteroaryl, which in one variation is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation of formula (L-6), R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-6), R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-6), R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation of formula (L-6), R3 is 2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula (L-6), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is a substituted phenyl, a substituted or pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (L-7) are also detailed herein:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (L-1). In one variation of formula (L-7), R1 is an unsubstituted C1-C8 alkyl (e.g., methyl, ethyl or isopropyl). In another variation of formula (L-7), R2 is unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variation of formula (L-7), R1 is an unsubstituted C1-C8 alkyl and R2 is unsubstituted C1-C8 alkyl or halo. In another variation of formula (L-7), R1 and R2 are independently an unsubstituted C1-C8 alkyl. In one variation of formula (L-7), R3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, such as those listed herein for formula (L-1). For example, compounds of the formula (L-7) are intended wherein R3 is a substituted aryl, which in one aspect it is a substituted phenyl. When R3 is a substituted phenyl, the phenyl may be substituted with one or more than one substituent. For example, on one variation, R3 is a monosubstituted phenyl where the substituent is a halo group. In another variation, R3 is a disubstituted phenyl substituent with two halo groups which may be the same or different. In a particular variation, R3 is 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds of formula (L-7) are also provided where R3 is an unsubstituted heteroaryl, which in one variation is a heteroaryl containing an annular nitrogen atom. In one aspect, when R3 is unsubstituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation of formula (L-7), R3 is an unsubstituted heteroaryl selected from pyridyl or pyrimidinyl and wherein such groups may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-7), R3 is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R3 is a substituted heteroaryl in one aspect it is a substituted pyridyl. When R3 is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (L-7), R3 is a monosubstituted pyridyl where the substituent is a C1-C8unsubstituted alkyl (e.g., methyl). In a particular variation of formula (L-7), R3 is 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula (L-7), R1 is an unsubstituted C1-C8 alkyl, R2 is unsubstituted C1-C8 alkyl or halo and R3 is a substituted phenyl, a substituted or pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (L-8) are also provided:




or a salt or solvate thereof, where R1, R2 and R3 are as defined for formula (L-1). In one variation of formula (L-8), R1 and R2 are each a C1-C8 unsubstituted alkyl group. In another variation of formula (L-8), R3 is an unsubstituted heteroaryl such as pyridyl. In a particular variation of formula (L-8), R1 and R2 are each a C1-C8 unsubstituted alkyl group and R3 is an unsubstituted heteroaryl.

Examples of compounds according to the invention are depicted in Table 2C. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.







TABLE 2C







Representative Compounds According to the Invention.










Compound
Structure







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Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation.
A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. Taking compound 1 as an example, a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity.
In one variation, compounds of the invention are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing compounds of the invention in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound of the invention are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein, such as compound 11.
Strikingly, it has been discovered that compounds included in the invention that contain a substituted vinyl moiety, such as methylvinyl, exhibit a lower binding affinity to H1 as compared to their unsubstituted vinyl counterparts. Thus, it is believed that substituted vinyl moieties, such as methylvinyl, may be responsible for reduced H1 affinity.
Compounds that exhibit affinity for the histamine receptor H1 may induce undesirable side effects, such as metabolic syndrome, diabetes type 2, weight gain, hyperlipidemia, hyperglycemia, hypertension and drowsiness (Kroeze et al., Neuropsychopharmacology (2003) 28, 519-526). The number and extent of undesirable side effects increases with increasing affinity for the H1 receptor. Thus, in one aspect, compounds of the formulae herein display reduced, low or no affinity to histamine receptor H1. Compounds with low affinity to H1 are those compounds which display less than about 80% inhibition of binding of a ligand to H1. Inhibition of binding of a ligand to H1 for all variations detailed herein is determined by a suitable assay known in the art such as the assay described herein. In some variations, compounds of the formulae herein inhibit binding of a ligand to H1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50%. In one variation, compounds of the formulae herein inhibit binding of a ligand to H1 by between about 50% to about 80%. In aspect, compounds of the formulae herein inhibit binding of a ligand to H1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50% at any concentration, such as those detailed herein, e.g., 0.1 μM and 1 μM. In one variation, compounds of the formulae herein inhibit binding of Pyrilamine to H1 as determined in the assay described herein. In a further variation, percent inhibition of binding to H1 is measured by assays detailed herein.
Compounds containing a substituted vinyl moiety, such as methylvinyl moiety, are detailed herein wherein the compounds exhibit reduced H1 affinity as compared to their unsubstituted vinyl counterparts. In one aspect, compounds that contain a substituted vinyl moiety, such as a methylvinyl moiety, exhibit low or no H1 affinity and thus provide compounds with fewer or lesser undesirable side effects than compounds containing an unsubstituted vinyl moiety. In one variation, compounds as detailed herein containing a substituted vinyl moiety, such as methylvinyl, inhibit binding of a ligand to H1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50%. In another variation, compounds as detailed herein containing a substituted vinyl moiety, such as methylvinyl, inhibit binding of a ligand to H1 by less than about any of 50%, 40%, 30%, 20%, 10% and 5%.
General Description of Biological Assays
The binding properties of compounds disclosed herein to a panel of aminergic G protein-coupled receptors including adrenergic receptors, dopamine receptors, serotonin receptors, histamine receptors and an imidazoline receptor may be determined. Binding properties may be assessed by methods known in the art, such as competitive binding assays. In one variation, compounds are assessed by the binding assays detailed herein. Compounds disclosed herein may also be tested in cell-based assays or in in vivo models for further characterization. In one aspect, compounds disclosed herein are of any formula detailed herein and further display one or more of the following characteristics: inhibition of binding of a ligand to an adrenergic receptor (e.g., α1D, α2A and α2B), inhibition of binding of a ligand to a serotonin receptor (e.g., 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7), inhibition of binding of a ligand to a dopamine receptor (e.g., D2L), and inhibition of binding of a ligand to a histamine receptor (e.g., H1, H2 and H3); agonist/antagonist activity to a serotonin receptor (e.g., 5-HT2A, 5-HT6); agonist/antagonist activity to a dopamine receptor (e.g., D2L, D2S); agonist/antagonist activity to a histamine receptor (e.g., H1); activity in a neurite outgrowth assay; efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction; efficacy in a preclinical model of attention impulsivity and executive function, and efficacy in a preclinical model of schizophrenia.
In one variation, inhibition of binding of a ligand to a receptor is measured in the assays described herein. In another variation, inhibition of binding of a ligand is measured in an assay known in the art. In one variation, binding of a ligand to a receptor is inhibited by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by greater than about any one of 80%, 85%, 90%, 95%, 100%, or between about 85% and about 95% or between about 90% and about 100% as determined in a suitable assay known in the art such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by at least about 80%±20% as determined in an assay known in the art.
In one variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein (e.g. α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2, H1, H2, H3). In one variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein (e.g. α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-T6, 5-HT7, D2L, H1, H2, H3). In one variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors detailed herein and further displays agonist or antagonist activity to one or more receptors detailed herein (e.g., serotonin receptor 5-HT2A, serotonin receptor 5-HT6, dopamine receptor D2L, and dopamine receptor D2S and histamine receptor H1) as measured in the assays described herein. In one variation, agonist response of serotonin receptor 5-HT2A is inhibited by compounds of the invention by at least about any one of 50%, 50%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assay such as the assay described herein.
In one variation, a compound of the invention displays the above described neurotransmitter receptor binding profile i.e. inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein and further stimulates neurite outgrowth, e.g. as measured by the assays described herein. Certain compounds of the invention showed activity in neurite outgrowth assays using primary neurons in culture. Data is presented indicating that a compound of the invention has activity comparable in magnitude to that of naturally occurring prototypical neurotrophic proteins such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Notably, neurite outgrowth plays a critical part of new synaptogenesis, which is beneficial for the treatment of neuronal disorders. In one variation, neuronal disorders include ADHD. In one variation, neurite outgrowth is observed with a potency of about 1 μM as measured in a suitable assay known in the art such as the assays described herein. In another variation, neurite outgrowth is observed with a potency of about 500 nM. In a further variation, neurite outgrowth is observed with a potency of about 50 nM. In another variation, neurite outgrowth is observed with a potency of about 5 nM.
In another variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein, further displays agonist or antagonist activity to one or more receptors detailed herein and further stimulates neurite outgrowth.
In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein and/or display the above described neurotransmitter receptor binding profile and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction, and in preclinical models of attention impulsivity and executive function, i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction. Compounds of the invention have been shown to be effective in a preclinical model of memory dysfunction associated with cholinergic hypofunction. As H1 antagonism may contribute to sedation, weight gain and reduced cognition, low affinity (less than about 80% inhibition of binding of Pyrilamine at 1 μM in the assay described herein) for this receptor may be associated with pro-cognitive effects and a more desirable side effect profile. Furthermore, compounds of the invention with increased potency as a 5-HT6 antagonist may have cognition-enhancing effects as serotonin acting through this receptor may impair memory.
In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, in preclinical models of attention impulsivity and executive function, and further displays agonist or antagonist activity to one or more receptors detailed herein.
In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, in preclinical models of attention impulsivity and executive function, and further stimulates neurite outgrowth.
In another variation, a compound of the invention inhibits at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, in preclinical models of attention impulsivity and executive function, and further displays agonist or antagonist activity to one or more receptor detailed herein and further stimulates neurite outgrowth.
In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors and further possesses anti-psychotic effects as measured in a preclinical model of schizophrenia, i.e., shows efficacy in a preclinical model of schizophrenia.
In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia and further displays agonist or antagonist activity to one or more receptors detailed herein.
In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia and further stimulates neurite outgrowth.
In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, in preclinical models of attention impulsivity and executive function, and further shows efficacy in a preclinical model of schizophrenia.
In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further displays agonist or antagonist activity to one or more receptors detailed herein and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function.
In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function.
In a further variation, a compound of the invention inhibits binding to at least one and as many as eleven receptors detailed herein, further displays agonist or antagonist activity to one or more receptors detailed herein, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of schizophrenia.
In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further displays agonist or antagonist activity to one or more receptors detailed herein, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function.
In another variation, a compound of the invention stimulates neurite outgrowth. In another variation, a compound of the invention shows efficacy in a preclinical model of schizophrenia and further stimulates neurite outgrowth. In another variation, a compound of the invention stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function. In another variation, a compound of the invention shows efficacy in a preclinical model of schizophrenia, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function.
In one aspect, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, αα2B and inhibit binding of a ligand to serotonin receptor 5-HT6. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, αα2A, α2B, to serotonin receptor 5-HT6 and to any one or more of the following receptors: serotonin receptor 5-HT7, 5-HT2A and 5-HT2C. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, α2B, to serotonin receptor 5-HT6 and to any one or more of the following receptors: serotonin receptor 5-HT7, 5-HT2A and 5-HT2C and further show weak inhibition of binding of a ligand to histamine receptor H1 and/or H2. In one variation, compounds of the invention that also display strong inhibition of binding of a ligand to the serotonin receptor 5-HT7 are particularly desired. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, α2B, to serotonin receptor 5-HT6 and further show weak inhibition of binding of a ligand to histamine receptor H1 and/or H2. Weak inhibition of binding of a ligand to the histamine H1 receptor is permitted as agonists of this receptor have been implicated in stimulating memory as well as weight gain. In one variation, binding to histamine receptor H1 is inhibited by less than about 80%. In another variation, binding of a ligand to histamine receptor H1 is inhibited by less than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined by a suitable assay known in the art such as the assays described herein.
In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D2. In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D2 and to serotonin receptor 5-HT2A. In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D2L. In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D2L and to serotonin receptor 5-HT2A.
In another variation, compounds of the invention inhibit binding of a ligand to histamine receptor H1. In certain aspects, compounds of the invention further show one or more of the following properties: strong inhibition of binding of a ligand to the serotonin 5-HT7 receptor, strong inhibition of binding of a ligand to the serotonin 5-HT2A receptor, strong inhibition of binding of a ligand to the serotonin 5-HT2C receptor, weak inhibition of binding of a ligand to the histamine H1 receptor, weak inhibition of binding of ligands to the histamine H2 receptor, and antagonist activity to serotonin receptor 5-HT2A.
In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further display agonist/antagonist activity to one or more of the following receptors: serotonin receptor 5-HT2A, serotonin receptor 5-HT6, dopamine receptor D2L, dopamine receptor D2S and histamine receptor H1. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further stimulate neurite outgrowth. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as enhancement of memory retainment and reduction of memory impairment, and in preclinical models of attention impulsivity and executive function. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in a preclinical model of schizophrenia. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in any one or more of agonist/antagonist assays (e.g., to serotonin receptor 5-HT2A, 5-HT6, dopamine receptor D2L, dopamine receptor D2S and histamine receptor H1), neurite outgrowth, a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction and a preclinical model of schizophrenia.
In some aspects, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, α2B, serotonin receptor 5-HT6 and dopamine receptor D2 by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation binding is inhibited by at least about 80% as measured in a suitable assay such as the assays described herein. In some aspects, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, α2B, serotonin receptor 5-HT6 and dopamine receptor D2L by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation binding is inhibited by at least about 80% as measured in a suitable assay such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by greater than about any one of 80%, 85%, 90%, 95%, 100%, or between about 85% and about 95%, or between about 90% and about 100% as determined in a suitable assay known in the art such as the assays described herein.
In some aspects, compounds of the invention display the above described neurotransmitter receptor binding profile and further show antipsychotic effects. It is recognized that compounds of the invention have binding profiles similar to compounds with antipsychotic activity and several compounds of the invention have been shown to be effective in a preclinical model of schizophrenia. In addition, compounds of the invention might possess the cognitive enhancing properties of dimebon and thus add to the beneficial pharmacology profile of these antipsychotic molecules. In one variation, compounds of the invention display the above described neurotransmitter receptor binding profile and further show pro-cognitive effects in a preclinical model of memory dysfunction such as enhancement of memory retention and reduction of memory impairment. In another variation, compounds of the invention display the above described neurotransmitter receptor binding profile and do not show pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory.
In one variation, compounds of the invention demonstrate pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory. In a further variation, compounds of the invention possess anti-psychotic effects in a preclinical model of schizophrenia. In a further variation, compounds of the invention demonstrate pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory and further possess anti-psychotic effects in a preclinical model of schizophrenia.
Overview of the Methods
The compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders in individuals, such as humans. In one aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a cognitive disorder. In one aspect, cognitive disorders include ADHD. In one variation, cognitive disorder as used herein includes and intends disorders that contain a cognitive component, such as psychotic disorders (e.g., schizophrenia) containing a cognitive component (e.g., CIAS). In another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a psychotic disorder. In one variation, psychotic disorder as used herein includes and intends disorders that contain a psychotic component, for example cognitive disorders (e.g., Alzheimer's disease) that contain a psychotic component (e.g., psychosis of Alzheimer's Disease or dementia). In one variation, methods of improving at least one cognitive and/or psychotic symptom associated with schizophrenia are provided. In one aspect, methods of improving cognition in an individual who has or is suspected of having CIAS are provided. In a particular aspect, methods of treating schizophrenia are provided wherein the treatment provides for an improvement in one or more negative symptom and/or one or more positive symptom and/or one or more disorganized symptom of schizophrenia. In yet another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a neurotransmitter-mediated disorders disorder. In one aspect, neurotransmitter-mediated disorders include ADHD. In one embodiment, the neurotransmitter-mediated disorder includes spinal cord injury, diabetic neuropathy, allergic diseases (including food allergies) and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). In another variation, the neurotransmitter-mediated disorder includes spinal cord injury, diabetic neuropathy, fibromyalgia and allergic diseases (including food allergies). In still another embodiment, the neurotransmitter-mediated disorder includes Alzheimer's disease, Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mild cognitive impairment, multiple sclerosis, stroke and traumatic brain injury. In yet another embodiment, the neurotransmitter-mediated disorder includes schizophrenia, anxiety, bipolar disorders, psychosis and depression and ADHD. In one variation, depression as used herein includes and intends treatment-resistant depression, depression related to a psychotic disorder, or depression related to a bipolar disorder. In another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a neuronal disorder. In one aspect, the compounds described herein may also be used to treat, prevent, delay the onset and/or delay the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial.
The invention also provides methods of improving cognitive functions and/or reducing psychotic effects comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to improve cognitive functions and/or reduce psychotic effects. In a particular variation, a method of treating schizophrenia is provided, wherein the treatment provides an improvement in at least one cognitive function, such as an improvement in a cognitive function in an individual who has or is suspected of having CIAS. In a further variation, a method of treating schizophrenia is provided wherein the method reduces psychotic effects associated with schizophrenia. In one embodiment, a method of treating schizophrenia is provided wherein the method improves the negative symptoms of schizophrenia in an individual in need thereof. In one embodiment, a method of treating schizophrenia is provided wherein the method improves the positive symptoms of schizophrenia in an individual in need thereof. In a further variation, a method of treating schizophrenia is provided wherein the method both improves cognitive function and reduces psychotic effects in an individual in need thereof. A method of improving one or more negative, positive and disorganized symptoms of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In one variation, a method of improving at least one negative symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In another variation, a method of improving at least one negative and at least one positive symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In yet another variation, a method of improving at least one negative and at least one disorganized symptom of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In still another variation, a method of improving at least one positive and at least one disorganized symptom of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In still a further variation, a method of improving at least one negative, at least one positive and at least one disorganized symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement.
The invention also provides methods of stimulating neurite outgrowth and/or promoting neurogenesis and/or enhancing neurotrophic effects in an individual comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and/or to promote neurogenesis and/or to enhance neurotrophic effects.
The invention further encompasses methods of modulating an aminergic G protein-coupled receptor comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to modulate an aminergic G protein-coupled receptor.
It is to be understood that methods described herein also encompass methods of administering compositions comprising the compounds of the invention.
Methods for Treating, Preventing, Delaying the Onset, and/or Delaying the Development Cognitive Disorders, Psychotic Disorders, Neurotransmitter-Mediated Disorders and/or Neuronal Disorders
In one aspect, the invention provides methods for treating, preventing, delaying the onset, and/or delaying the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial, the method comprising administering to an individual in need thereof a compound of the invention. In some variations, modulation of adrenergic receptor α1D, α2A, α2B, serotonin receptor 5-HT2A, 5-HT6, 5-HT7, histamine receptor H1 and/or H2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of adrenergic receptor α1D, α2A, α2B and a serotonin receptor 5-HT6 receptor is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of adrenergic receptor α1D, α2A, α2B, and a serotonin receptor 5-HT6 receptor and modulation of one or more of the following receptors serotonin 5-HT7, 5-HT2A, 5-HT2C and histamine H1 and H2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of a dopamine receptor D2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of dopamine receptor D2L is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In certain variations, modulation of a dopamine D2 receptor and serotonin receptor 5-HT2A is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In certain variations, modulation of a dopamine D2L receptor and serotonin receptor 5-HT2A is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders are treated, prevented and/or their onset or development is delayed by administering a compound of the invention.
Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects
The invention provides methods for improving cognitive functions by administering a compound of the invention to an individual in need thereof. In some variations, modulation of one or more of adrenergic receptor α1D, α2A, α1D, serotonin receptor 5-HT2A, 5-HT6, 5-HT7, histamine receptor H1 and/or H2 is desirable or expected to be desirable to improve cognitive functions. In some variations modulation of α1D, α2A, α2B adrenergic receptors and a serotonin 5-HT6 receptor is desirable or expected to be desirable to improve cognitive functions. In some variations, modulation of α1D, α2A, α2B adrenergic receptors and serotonin receptor 5-HT6 and modulation of one or more of the following receptors: serotonin receptor 5-HT7, 5-HT2A, 5-HT2C and histamine receptor H1 and H2, is desirable or expected to be desirable to improve cognitive functions. In another aspect, the invention encompasses methods to reduce psychotic effects by administering a compound of the invention to an individual in need thereof. In some embodiments, modulation of a dopamine D2 receptor is expected to be or is desirable to reduce psychotic effects. In some embodiments, modulation of a dopamine D2L receptor is expected to be or is desirable to reduce psychotic effects. In some embodiments, modulation of a dopamine D2 receptor and a serotonin 5-HT2A receptor is expected to be or is desirable to reduce psychotic effects. In some variations, a compound of the invention is administered to an individual in need thereof. In some embodiments, modulation of a dopamine D2L receptor and a serotonin 5-HT2A receptor is expected to be or is desirable to reduce psychotic effects. In some variations, a compound of the invention is administered to an individual in need thereof.
Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/or Enhance Neurotrophic Effects
In a further aspect, the invention provides methods of stimulating neurite outgrowth and/or enhancing neurogenesis and/or enhancing neurotrophic effects comprising administering a compound of the invention or pharmaceutically acceptable salt thereof under conditions sufficient to stimulate neurite outgrowth and/or to enhance neurogenesis and/or enhance neurotrophic effects to an individual in need thereof. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 1 μM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 500 nM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 50 nM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 5 nM as measured in a suitable assay such as the assays described herein.
Methods to Modulate an Aminergic G Protein-Coupled Receptor
The invention further contemplates methods for modulating the activity of an aminergic G-protein-coupled receptor comprising administering a compound of the invention or pharmaceutically acceptable salt thereof under conditions sufficient to modulate the activity of an aminergic G protein-coupled receptor. In some variations, the aminergic G protein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and a serotonin 5-HT6 receptor. In some variations, the aminergic G protein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and a serotonin 5-HT6 and 5-HT7 receptor. In some variations, the aminergic G protein-coupled receptor is a α1D, α2A, α2B adrenergic receptor, a serotonin 5-HT6 and one or more of the following receptors: serotonin 5-HT7, 5-HT2A and 5-HT2C and histamine H1 and H2 receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D2L receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D2L receptor and a serotonin 5-HT2A receptor. In some variations, the aminergic G protein-coupled receptor is a histamine H1 receptor.
Dose-Dependent Therapy (DDT)
Dose dependent therapy refers to the concept that a single molecule may be used for different indications depending on the dose at which it is administered. It has been shown that compounds included in the invention exert pro-cognitive effects (where in one aspect pro-cognitive effects are achieved by reducing one or more symptoms associated with impaired cognition) when administered at low dose, whereas at high dose, these compounds induce both pro-cognitive and anti-psychotic effects (where in one aspect anti-psychotic effects are achieved by reducing one or more symptoms associated with a psychotic disorder). These compounds are further referred to as Dose-Dependent Therapy compounds (DDT compounds). When administered at high dose, DDT compounds in one aspect show fewer and/or lesser side-effects such as, e.g., extrapyramidal syndrome (EPS), as compared to other anti-psychotics, such as anti-psychotics which are not 5-HT2A receptor modulators. It is believed that EPS is caused, at least in part, by high D2 receptor occupancy, the effect of which can be counteracted by compounds displaying a high affinity to the serotonin receptor 5-HT2A. EPS can be determined using various scales known in the art such as the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Rating Scale (SARS), Extrapyramidal Symptoms Rating Scale (ESRS) and the Extrapyramidal Symptoms Rating Scale-Abbreviated (ESRS-A). DDT compounds in one aspect are 5-HT2A modulators, and preferably are antagonists of 5-HT2A. In one variation, DDT compounds have low or no affinity for the histamine receptor H1, which is also implicated in undesirable side effects such as metabolic syndrome, diabetes type 2, weight gain, hyperlipidemia, hyperglycemia, hypertension and drowsiness (Kroeze et al., Neuropsychopharmacology (2003) 28, 519-526).
DDT Compounds
DDT compounds modulate at least serotonin receptor 5-HT2A and/or serotonin receptor 5-HT6 and modulate dopamine receptor D2, such as D2L. In one aspect, DDT compounds inhibit binding of a ligand to at least 5-HT2A and/or 5-HT6 and binding of a ligand to D2. Inhibition of binding for all variations detailed herein is determined in a suitable assay known in the art, such as the assays described herein. In one aspect, DDT compounds act as antagonists of 5-HT2A and/or 5-HT6 and act as antagonists of D2. In another aspect, DDT compounds act as antagonists of 5-HT2A and D2. In another aspect, DDT compounds act as antagonists of 5-HT2A, 5-HT6 and D2. In one variation, DDT compounds inhibit binding of a ligand to 5-HT2A and/or 5-HT6 by at least about 50% at a DDT concentration of about 0.1 μM and inhibit binding of a ligand to D2 by at least about 90% at a DDT concentration of about 1 μM. In another variation, DDT compounds inhibit binding of a ligand to 5-HT2A and/or 5-HT6 by greater than about any of 50%, 60%, 70% or 80% at a DDT concentration of at least about 0.1 μM. In a further variation, DDT compounds inhibit binding of a ligand to 5-HT2A and/or 5-HT6 by greater than about any of 50%, 60%, 70% or 80% at a DDT concentration of less than about 0.1 μM (e.g., greater than about 0.01 μM and less than about 0.1 μM). In a further variation, DDT compounds inhibit binding of a ligand to 5-HT2A and/or 5-HT6 by at least about 80% at a DDT concentration of about 0.1 μM. In one variation, DDT compounds inhibit binding of a ligand to D2 by at least about 90% at a DDT concentration of greater than about 1 μM. In another variation, DDT compounds inhibit binding of a ligand to D2 by at least about 90% at a DDT concentration of between about 1 μM to about 3 μM. In one variation, DDT compounds inhibit binding of Ketanserin, LSD and Spiperone to 5-HT2A, 5-HT6 and D2, respectively, as determined in the assays described herein. In another variation, binding of a ligand to 5-HT2A and/or 5-HT6 is inhibited by greater than about any of 80%, 85%, 90% or 95%, or by about 100% at a DDT concentration of about 0.1 μM. In a further variation, binding of a ligand to 5-HT2A and/or 5-HT6 is inhibited between about 85% to about 95% or between about 90% to about 100% at a DDT concentration of about 0.1 μM. In another variation, binding of a ligand to D2 is inhibited by greater than about any of 90% and 95%, or by about 100% at a DDT concentration of about 1 μM. In a further variation, binding of a ligand to D2 is inhibited by between about 90% to about 100% at a concentration of about 1 μM. In another variation, inhibition of binding of a ligand to 5-HT2A and/or 5-HT6 is at least 80%±20% at a DDT concentration of about 0.1 μM and binding of a ligand to D2 is inhibited by at least about 90% at a concentration of about 1 μM as determined in assays known in the art. In one aspect, DDT compounds inhibit binding of a ligand to 5-HT2A and D2. In another aspect, DDT compounds inhibit binding of a ligand to 5-HT6 and D2. In yet another aspect, DDT compounds inhibit binding of a ligand to 5-HT2A, 5-HT6 and D2. In one variation, percent inhibition of binding to 5-HT2A, 5-HT6 and D2 is measured by assays detailed herein.
In one aspect, DDT compounds display low affinity to histamine receptor H1. Compounds with low affinity to H1 are those compounds which display less than about 80% inhibition of binding of a ligand to H1. Inhibition of binding of a ligand to H1 for all variations detailed herein is determined by a suitable assay known in the art such as the assay described herein. In some variations, DDT compounds inhibit binding of a ligand to H1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% or 50%. In one variation, DDT compounds inhibit binding of a ligand to H1 by between about 50% to about 80%. In some variations, DDT compounds inhibit binding by less than about 80% at any DDT concentration, e.g., at about 0.1 μM to about 1 μM. In one variation, DDT compounds inhibit binding of Pyrilamine to H1 as determined in the assay described herein. In a further variation, percent inhibition of binding to H1 is measured by assays detailed herein.
In some aspects, DDT compounds act as 5-HT2A and D2 antagonists. Antagonist activity for all variations is measured in suitable assays known in the art such as the assays described herein. In one variation, 5-HT2A activity is inhibited by at least about 70% at a DDT concentration of about 0.1 μM. In another variation, 5-HT2A activity is inhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, or 95%, or by about 100% at a DDT concentration of about 0.1 μM. In one variation, D2 activity is inhibited by at least about 70% at a DDT concentration of about 1 μM. In another variation, D2 activity is inhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, or 95%, or by about 100% at a DDT concentration of about 1 μM. In one variation, percent inhibition of activity is determined in the assays described herein. In one aspect, DDT compounds inhibit 5-HT2A and D2 activity. In another aspect, DDT compounds inhibit 5-HT2A, 5-HT6 and D2 activity.
In one aspect, DDT compounds display any of the activities detailed herein for DDT compounds and further have a structure of the formulae provided herein. In one aspect, DDT compounds contain a substituted vinyl moiety, such as a methylvinyl moiety. Accordingly, in a particular aspect, DDT compounds are of the formula (C), or any variation thereof, including compounds of the formula (C), where at least one of R8d and R8f is other than H, such as when at least one of R8d and R8f is a C1-C8 alkyl, C3-C8 cycloalkyl, or C1-C8 perhaloalkyl. DDT compounds may also be of the formulae (X-1), (X-1a), (X-1b), (X-2), (X-2a), (X-2b), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9) or (X-10), or any variation thereof. DDT compounds may also be of the formulae (C-1), (C-1a), (C-1b), (C-2), (C-2a), (C-2b), (C-3a), (C-3b), (C-4a), (C-4b), (C-5a), (C-5b), (C-6a) or (C-6b).
DDT compounds may be present as pharmaceutically acceptable salts, or solvates thereof. Pharmaceutical compositions comprising a DDT compound and a pharmaceutically acceptable carrier are also embraced. These pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
High Dose
In one aspect, high dose of a DDT compound corresponds to an amount that results in at least 65% of receptor occupancy of dopamine receptor D2, which may be assessed by known methods, such as Positron Emission Tomography (PET) (Pani et al., European Psychiatry (2007) 22, 276-275). In some variations, a high dose provides D2 occupancy that is greater than any one of 65%, 70%, 75%, 80%, 85% and 90%. In one variation, a high dose provides D2 occupancy that is at least 65%. In another variation, a high dose provides a D2 occupancy that is from at least 65% to 90%, or from at least 65% to 85%, or from at least 65% to 80%, or from at least 65% to 75%, or from at least 65% to 70%, or from at least 70% to 90%, or from at least 70% to 85%, or from at least 70% to 80%, or from at least 70% to 75%, or from at least 75% to 90%, or from at least 75% to 85%, or from at least 75% to 80%, or from at least 80% to 90%. In one variation, a high dose provides D2 occupancy that is less than 80% and greater than 65%.
In another aspect, high dose of a DDT compound corresponds to a daily dose of at least about 1 mg/kg. In another variation, high dose corresponds to a daily dose of about 1 mg/kg. In another variation, high dose corresponds to a daily dose of at least about 1 mg/kg to at least about 3 mg/kg. In yet another variation, high dose corresponds to a daily dose of at least about 1 mg/kg to about 5 mg/kg. In a further variation, high dose corresponds to a daily dose of greater than 1 mg/kg.
In a further aspect, high dose of a DDT compound corresponds to an amount that induces anti-psychotic effects as determined by the Positive and Negative Syndrome Scale (PANSS). In another variation, anti-psychotic effects are measured by one or more of the following: PANSS, Brief Psychiatric Rating Scale (BPRS), Positive symptom sub-scale of PANSS, Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). In a further variation, anti-psychotic effects are measured by another scale and/or test known in the art.
In another aspect of the invention, high dose of a DDT compound corresponds to at least about 100 times the amount that induces pro-cognitive effects but does not induce anti-psychotic effects. In one variation, pro-cognitive effects are determined by cognition scales known in the art such as the Measurement and Treatment Research to Improve Cognition in Schizophrenia MATRICS. In another variation, pro-cognitive effects are determined by measuring the cognitive components of one or more of the following scales and/or tests: MATRICS, Negative Symptoms Assessment scale (NSA), Scale for the Assessment of Negative Symptoms (SANS), Schedule for the Deficit Syndrome (GDS), Negative symptom sub-scale of PANSS, MATRICS Consensus Cognition Battery (MCCB), CNSVitalSigns, CogState battery, Cognitive Drug Research battery (CDR), Brief Assessment of Cognition in Schizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS), Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Test of Adaptive Behavior in Schizophrenia (TABS), Independent Living Skills Inventory (ILS), UCSD Performance-Based Skills Assessment (UPSA), Cognitive Assessment Interview (CAI), Global Assessment of Function from CAI (GAF), Quality of Life Scale (QLS), Maryland Assessment of Social Competence (MASC), Calgary Depression Scale (CDS), and Montgomery-Åsberg Depression Rating Scale (MADRS). In a further variation, pro-cognitive effects are determined by another scale and/or test known in the art.
Low Dose
In one aspect, low dose of a DDT compound corresponds to an amount that results in less than 65% receptor occupancy of dopamine receptor D2. In some variations, a low dose provides D2 occupancy that is less than any one of 65%, 60%, 55% and 50%.
In another aspect, low dose of a DDT compound corresponds to a daily dose of about 0.03 mg/kg. In another variation, low dose corresponds to a daily dose of about 0.03 to about 0.3 mg/kg. In another variation, low dose corresponds to a daily dose of about 0.3 mg/kg. In yet another variation, low dose corresponds to a daily dose of about 0.03 to about 1 mg/kg. In a further variation, low dose corresponds to a daily dose of about 0.01 mg/kg. In yet another variation, low dose corresponds to a daily dose of 0.01 to about 1 mg/kg. In a further variation, low dose corresponds to a daily dose of about 0.5 mg/kg. In yet another variation, low dose corresponds to a daily dose of less than about 0.5 mg/kg. In another variation, low dose corresponds to a daily dose of less than 1 mg/kg.
In a further aspect, low dose of a DDT compound corresponds to an amount that induces pro-cognitive effects as determined by cognition scales such as MATRICS but does not induce anti-psychotic effects. In another variation, pro-cognitive effects are determined by measuring the cognitive components of one or more of the following scales and/or tests: MATRICS, Negative Symptoms Assessment scale (NSA), Scale for the Assessment of Negative Symptoms (SANS), Schedule for the Deficit Syndrome (GDS), Negative symptom sub-scale of PANSS, MATRICS Consensus Cognition Battery (MCCB), CNSVitalSigns, CogState battery, Cognitive Drug Research battery (CDR), Brief Assessment of Cognition in Schizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS), Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Test of Adaptive Behavior in Schizophrenia (TABS), Independent Living Skills Inventory (ILS), UCSD Performance-Based Skills Assessment (UPSA), Cognitive Assessment Interview (CAI), Global Assessment of Function from CAI (GAF), Quality of Life Scale (QLS), Maryland Assessment of Social Competence (MASC), Calgary Depression Scale (CDS), and Montgomery-Åsberg Depression Rating Scale (MADRS). In a further variation, pro-cognitive effects are determined by another scale and/or test known in the art.
In another aspect of the invention, low dose of a DDT compound corresponds to at least about 1/100 the amount that induces anti-psychotic effects. In one variation, anti-psychotic effects are determined by assays such as PANSS. In another variation, anti-psychotic effects are measured by one or more of the following: PANSS, Brief Psychiatric Rating Scale (BPRS), Positive symptom sub-scale of PANSS, Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). In a further variation, anti-psychotic effects are measured by another scale and/or test known in the art.
Unit Dosage Forms
DDT compounds may be provided in various unit dosage forms. In one aspect, single therapy dosages are provided. In one variation, a unit dosage form comprises a low dose as described herein of a DDT compound. In another variation, a unit dosage form comprises a high dose as described herein of a DDT compound.
In another aspect, combination therapy dosage forms are provided. In one variation, combination dosage forms comprise a low dose as described herein of a DDT compound and a second drug suitable for anti-psychotic therapy. In another variation, combination dosage forms comprise a high dose as described herein of a DDT compound and a second drug suitable for anti-psychotic therapy.
Kits
The present invention further provides for kits comprising DDT compounds with instructions for achieving pro-cognitive effects at low dose as detailed herein or pro-cognitive effects and anti-psychotic effects at high dose as detailed herein. In one aspect, kits comprise a low dose of a DDT compound and instructions for achieving only pro-cognitive effects. In some variations, pro-cognitive effects include (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood. Thus, kits for use to achieve pro-cognitive effects in one aspect comprise a low dose of a DDT compound as described herein. In another variation, kits for use to achieve pro-cognitive effects comprise a unit dosage form containing a low dose of a DDT compound as described herein.
In a further aspect, kits of the present invention comprise a high dose of a DDT compound and instructions for achieving both pro-cognitive and anti-psychotic effects. In some variations, anti-psychotic effects comprise improvement of any one or more of psychotic symptoms such as positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized thought and agitation). Kits comprising a high dose of a DDT compound may be used to achieve one or more pro-cognitive effects and one or more anti-psychotic effects. Thus, kits for use to achieve pro-cognitive and anti-psychotic effects in one aspect comprise a high dose of a DDT compound as described herein. In another variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a unit dosage form containing a high dose of a DDT compound as detailed herein. In a further variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a low dose of a DDT compound and a second drug suitable for anti-psychotic therapy. In yet another variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a high dose of a DDT compound and a second drug suitable for anti-psychotic therapy. In one aspect, kits for use to achieve pro-cognitive and anti-psychotic effects comprise DDT compounds in unit dosage forms as detailed herein.
Methods of Treatment
The invention provides methods of treating diseases or conditions in which cognition and/or psychosis are implicated. The present invention provides methods of treating cognitive disorders and/or psychotic disorders by administering a DDT compound at a pharmaceutically effective dose to a subject in need thereof. In one variation, cognitive disorder as used herein includes and intends disorders that contain a cognitive component, such as psychotic disorders (e.g., schizophrenia) containing a cognitive component (e.g., CIAS). In one variation, a cognitive disorder is a disorder which affects executive function. In one variation, psychotic disorder as used herein includes and intends disorders that contain a psychotic component, for example cognitive disorders (e.g., Alzheimer's disease) that contain a psychotic component (e.g., psychosis of Alzheimer's Disease or dementia). In one variation, a psychotic disorder is psychosis associated with dementia.
In one aspect, the present invention encompasses methods of improving cognition by administering a DDT compound at a pharmaceutically effective dose to a subject in need thereof. In one variation, improving cognition comprises reducing one or more symptoms associated with impaired cognition. In a further aspect, the present invention provides methods of (i) improving cognition and (ii) reducing symptoms associated with psychotic disorders in a subject in need thereof. In yet another aspect, the present invention encompasses methods of improving cognition and not reducing symptoms associated with psychotic disorders in a subject in need thereof. In yet a further aspect, the present invention provides methods of improving cognition and not significantly reducing symptoms associated with psychotic disorders in a subject in need thereof. In some variations, a subject in need thereof is an individual who is refractory to other pro-cognitive and/or anti-psychotic therapy.
In one aspect, the invention is directed to methods of improving cognition and/or reducing symptoms associated with impaired cognition by administering a DDT compound at either low or high dose. In one variation improving cognition comprises (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood.
In a further aspect, the invention provides methods of both (i) improving cognition (e.g., as set forth herein) and/or reducing symptoms associated with impaired cognition and (ii) reducing symptoms associated with psychotic disorders by administering a DDT compound at high dose. In one variation, reducing symptoms associated with psychotic disorders comprises improvement of any one or more of psychotic symptoms such as positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized thought and agitation). In one variation, the invention is directed to methods of treating schizophrenia by administering a high dose of a DDT compound. In another variation, the invention provides methods of reducing one or more symptom of positive symptoms of schizophrenia by administering a high dose of a DDT compound. In a further variation, the invention encompasses methods of reducing one or more symptom of positive and/or one or more symptom of negative symptoms of schizophrenia by administering a high dose of a DDT compound. In yet another variation, the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of CIAS by administering a high dose of a DDT compound. In yet another variation, the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of negative symptoms and/or one or more of disorganized symptoms of schizophrenia by administering a high dose of a DDT compound.
In another aspect, the invention is directed to methods of improving cognition and/or reducing symptoms associated with impaired cognition and not reducing symptoms associated with psychotic disorders by administering a DDT compound at low dose. In one variation improving cognition comprises (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood.
In yet another aspect, the invention encompasses methods of improving cognition and/or reducing symptoms associated with impaired cognition without significantly improving symptoms associated with psychotic disorders by administering a DDT compound at low dose.
Methods of Manufacturing a Medicament
In a further aspect of the invention use of DDT compounds and compositions thereof in the manufacture of a medicament is provided. Particularly, the manufacture of a medicament for use in the treatment of diseases or conditions in which cognition and/or psychosis are implicated are described herein. Further, pharmaceutical compositions of DDT compounds are also intended for use in the manufacture of a medicament for use in treatment of diseases or conditions in which cognition and/or psychosis are implicated.
Method of Determining a Dose/Treatment
The present invention further encompasses methods of determining a suitable or optimal dose of a DDT compound to either (i) achieve pro-cognitive effects alone or (ii) achieve both pro-cognitive effects and anti-psychotic effects in an individual in need thereof. In one aspect, a suitable dose is determined by measuring the percentage of D2 occupancy and adjusting an individual's dosage in response thereto. In one variation, dosage is increased to achieve anti-psychotic effects if D2 occupancy is less than 65% as determined by methods known in the art such as PET. In another variation, dosage is increased to achieve anti-psychotic effects if D2 occupancy is less than any one of 65%, 60%, 55%, and 50%. In a further variation, dosage is reduced to achieve pro-cognitive and not anti-psychotic effects if D2 occupancy is at least 65%. In yet another variation, dosage is reduced to achieve pro-cognitive and not anti-psychotic effects if D2 occupancy is at greater than any one of 65%, 70%, 75%, 80% and 90%. In a further variation, dosage is reduced to achieve pro-cognitive and no significant anti-psychotic effects if D2 occupancy is greater than 65%. One indication of at least 65% D2 occupancy or greater than any one of 65%, 70%, 75%, 80% and 90% D2 occupancy is the reduction in the number or severity of one or more symptoms associated with a psychotic disorder.
In another aspect, a suitable dose is determined by assessing pro-cognitive and/or anti-psychotic effects in an individual and adjusting an individual's dosage in response thereto. For example, in one variation, an individual's dosage is increased from a first dosage to a higher, second dosage, in order to achieve anti-psychotic effects at the second dosage level, if it is determined that the first dosage does not induce anti-psychotic effects in the individual, as may be assessed by suitable test and/or scales known in the art. In another variation, dosage is reduced from a first dosage to a lower, second dosage wherein the second dosage still achieves anti-psychotic effects but reduces side effects as compared to the first dosage. Side effects may be determined by suitable tests and/or scales known in the art. In another variation, dosage is decreased from a first dosage to a lower, second dosage, in order to achieve pro-cognitive and not anti-psychotic effects. In another variation, dosage is decreased from a first dosage to a lower, second dosage, in order to achieve pro-cognitive and not anti-psychotic effects and wherein the dosage induces fewer or lesser side effects than the first dosage. Thus, in yet another variation, dosage is reduced to a minimum dosage which still achieves pro-cognitive effects but reduces side-effects as determined by suitable tests and/or scales.
In one aspect, an individual's therapy is monitored as set forth above for a period of time, such as one week, two weeks, three weeks, one month, two months, three months, four months, five months, 6 months or more (such as throughout the course of an individual's therapy), to adjust an individual's dosage level as needed. As such, individualized therapy as detailed herein provides for methods of measuring therapeutic parameters and adjusting dosage in response thereto in order to achieve an optimal dosage amount according to an individual's initial and continued response to therapy.
General Synthetic Methods
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof unless otherwise indicated.
Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
The following abbreviations are used herein: thin layer chromatography (TLC); Hour (h); Minute (min.); Second (sec.); Ethanol (EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); Retention factor (Rf).
A method of synthesizing an intermediate used in the synthesis of compounds of the invention is shown as General Method 1. Although identifiers such as R are shown in the methods below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere. It is also understood that modifications to the specific materials shown in the methods below are intended, e.g., where a method using a compound having an aryl group such as phenyl can likewise be can utilized with a compound having a heteroaryl group such as pyridyl to arrive at heteroaryl containing products.
General Method 1.




The 1-methylazepan-4-one hydrochloride (1 equiv.) and appropriately substituted arylhydrazine hydrochloride (1 equiv.) are refluxed in a mixture of 7% sulfuric acid in 1,4-dioxane (2-3 mL) overnight under nitrogen. The mixture is poured on to ice and basified with 50% aq NaOH. The resulting precipitate is filtered, washed well with water, and dried in air to provide the substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole derivative.
A method of synthesizing another intermediate used in the synthesis of compounds of the invention is shown as General Method 2.
General Method 2.




The appropriate aryl bromide (1 equiv.) is dissolved in DMF. Tributylvinyltin (1.1 equiv.) and Pd(PPh3)4 (0.02 equiv.) are added to this solution at RT under nitrogen and the reaction mixture is heated at 100° C. for 1.5 h. The reaction mixture is cooled to RT, diluted with water and extracted with DCM. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude product is purified through column chromatography in silica gel to provide the desired vinylarene derivative.
A method of synthesizing another intermediate used in the synthesis of compounds of the invention is shown as General Method 3.
General Method 3.




NaH (1 equiv.) is added to DMSO and heated to 65° C. for 1 h. THF is added at the same temperature and the reaction mixture is heated for another 10 min., after which the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) is then added and the reaction mixture is stirred for 10 min. The solution of appropriate ketone (1 equiv.) in THF is added dropwise. After completion of addition, the reaction mixture is stirred at RT for 2 h. The reaction mixture is poured into ice water and product extracted in diethyl ether, dried over Na2SO4 and concentrated at 25° C.
A method of synthesizing certain compounds of the invention is shown as General Method 4.
General Method 4.




A mixture of appropriately substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 equiv.), 2-trifluoromethyl-5-vinylpyridine (1.1 equiv.) and KOH (3.5 equiv.) in NMP (0.5 mL/mmol) is stirred and heated at 50-100° C. for 3 h. The reaction mixture is cooled to RT and diluted by adding ice and satd. aqueous NaCl. The aqueous mixture is extracted with ethyl acetate and organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product. The crude product is purified either by flash chromatography on silica gel or by reverse phase HPLC.
A method of synthesizing certain compounds of the invention is shown as General Method 5.
General Method 5.




The appropriately substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 equiv.) is dissolved in DMF (2 mL/mmol). To this solution sodium hydride (2.2 equiv.) is added in portions at RT and stirred for 10 min. The appropriate aryl oxirane (2 equiv.) in DMF (0.5 mL/mmol) is added dropwise over 10 min. and stirred overnight at RT. The product is detected by LCMS, and the reaction mixture is quenched with methanol and concentrated to dryness. Water is added to the residue and product is extracted into ethyl acetate (3×50 mL). The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product is purified by reverse phase chromatography.
A method of synthesizing certain compounds of the invention is shown as General Method 6.
General Method 6.




The appropriately substituted 2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol (1 equiv.) is taken into 25% aqueous H2SO4 (8 mL/mmol), and stirred at 90° C. for 3 h. The reaction is monitored by TLC and LCMS. The reaction mixture is cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product is purified using reverse phase chromatography.
A method of synthesizing certain compounds of the invention is shown as General Method 7.
General Method 7.




The appropriately substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 equiv.), is taken into DMF. CuI (0.1 equiv.), L-proline (0.2 equiv.) and K3PO4 (2 equiv.) are added to the solution and the mixture stirred for 10 min. at RT. The 2-haloacetamide derivative (1.2 equiv.) is added dropwise. The reaction mixture is heated at 90° C. for 12 h. After completion of reaction, the reaction mixture is filtered through Celite. DMF is evaporated under reduced pressure and then the residue extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product that is purified by column chromatography.
A method of synthesizing certain compounds of the invention is shown as General Method 8.
General Method 8.




Sodium hydride (1.5 equiv.) is washed with hexane for removal of oil and dried under vacuum. It is then suspended in THF. To this suspension carboline (1 equiv.) in THF is added dropwise at 0° C. Then the reaction mixture is stirred for 0.5 h. A solution of vinyl compound (2 equiv.) in THF is added dropwise into the reaction mixture. The reaction mixture is stirred at RT for 2 h and monitored by TLC. After completion of reaction, the reaction mixture is quenched with ice-water. The crude compound is purified by preparative TLC. The pure compound is stirred in ethanolic HCl to give the corresponding HCl salt.
A method of synthesizing certain compounds of the invention is shown as General Method 9.
General Method 9.




The substituted carboline (1 equiv.) is taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (0.2 equiv.) and K3PO4 (2 equiv.) are added to the solution and the mixture stirred for 10 min. at RT. The 2-chloroacetate (1.2 equiv.) is added dropwise. The reaction mixture is heated at 90° C. for 12 h. After completion of reaction, the reaction mixture is filtered through Celite. DMF is evaporated under reduced pressure and the residue extracted with ethyl acetate. The organic layer is dried over Na2SO4, and concentrated under reduced pressure. Then the purified compound is taken in ethanol in HCl to give HCl salt of desired compound.
A method of synthesizing another intermediate used in the synthesis of compounds of the invention is shown as General Method 10.
General Method 10.




The appropriately substituted azepan-4-one hydrochloride (1 equiv.) and appropriately substituted arylhydrazine hydrochloride (1 equiv.) are refluxed in a mixture of 7% sulfuric acid in 1,4-dioxane overnight under nitrogen. The mixture is poured on to ice and basified with 50% aq NaOH. The resulting precipitate is filtered, washed well with water, and dried in air to provide the substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole derivative.
A method of synthesizing compounds of the invention is shown in General Method 11.
General Method 11.




In general, a suitably substituted hydrazine A can be reacted with an appropriately substituted alkyl halide B to generate a substituted hydrazine C, where the internal nitrogen on the hydrazine is substituted, as shown above. The reaction of intermediate D with an appropriately substituted azepan-4-one D should provide structures of the type generally described by structure E.
General Method 12.




Appropriate alcohol-carboline (1 equiv.) is dissolved in DCM and the solution is cooled to 0° C. Diethylaminosulfur trifluoride (DAST) (1.5 equiv.) is added dropwise and the reaction mixture is stirred at RT for 2 h. The reaction mixture is diluted with saturated aqueous NaHCO3 solution and the organic layer is separated. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on neutral alumina to give the fluorinated product.




General Method 13

To a solution of appropriate carboline (1 equiv.) in N-methyl-2-pyrrolidone is added KOH (7 equiv.). The reaction mixture is stirred at RT for 20 min. A solution of appropriate 2-bromo-1-(aryl)ethanone (1 equiv.) in N-methyl-2-pyrrolidone is added dropwise and stirring is continued for additional 2-4 h. The reaction is monitored by LCMS and TLC. The reaction mixture is diluted by adding water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give the keto product.
General Method 14
The keto compound from General Method 13 (1 equiv.) is dissolved in anhydrous THF. Grignard reagent (3 equiv) is added to it dropwise at RT under nitrogen atmosphere and reaction mixture is stirred at RT for 1 h. Water is added to the reaction mixture and the product is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by HPLC to give pure alcohol product.




General Method 15

Appropriately substituted carboline (1 equiv.) is dissolved in DMF (2 mL per mmol) and sodium hydride (2 equiv.) is added to it under nitrogen atmosphere. An appropriate 2-(bromomethyl)-1,3-dioxolane (1 equiv.) is added and the reaction mixture is heated at 100° C. overnight. The reaction mixture is diluted by adding water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give pure dioxolanyl product.
The methods detailed above may be adapted as known by those of skill in the art. Particular examples of each General Method are provided in the Examples below. Additional synthetic methods which may be adapted to arrive at the compounds detailed herein are found in U.S. application Ser. No. 12/259,234 and PCT Application No. PCT/US2008/081390, both filed Oct. 27, 2008.
The following Examples are provided to illustrate but not limit the invention.
All references disclosed herein are incorporated by reference in their entireties.
EXAMPLES
Example 1
Preparation of 9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole
The title compound was prepared by following general procedure 1. 1-Methylazepan-4-one hydrochloride (164 mg, 1 mmol) and 4-chlorophenylhydrazine hydrochloride (179 mg, 1 mmol) were heated in a mixture of 7% sulfuric acid in 1,4-dioxane (2-3 mL) overnight under nitrogen. Two liquid layers persisted throughout the reaction. The mixture was poured on to ice and basified with 50% aq NaOH. The resulting precipitate was filtered, washed well with water, and dried in air to give 9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole as a dark brown solid (183 mg 78% yield).
Example 2
Preparation of 1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole
The title compound was prepared by following general procedure 1. p-Tolyl hydrazine hydrochloride (15 g, 94.55 mmol) was taken into 7% H2SO4 in 1,4-dioxane (650 mL), 1-methylazepan-4-one. HCl (15.4 g, 94.55 mmol) was added and stirred at RT for 10 min. The reaction mixture was stirred at 80° C. for 14 h. After completion of the reaction, reaction mass was slowly basified with 50% NaOH solution, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness and purified by column chromatography (silica gel 100-200 mesh; eluent: 10% methanol-DCM) to afford 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5 g).
Example 3
Preparation of 2-ethyl-5-vinyl-pyridine
The title compound was prepared by following general procedure 2. 2-Ethyl-5-bromopyridine (0.6 g, 0.00322 mol) was dissolved in DMF:THF (3:1 6 mL), and to this solution, tributylvinyltin (1.03 mL, 0.00354 mol) and Pd(PPh3)4 (0.048 g, 0.000041 mol) were added at RT under nitrogen and the mixture heated at 100° C. for 30 min. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-ethyl-5-vinylpyridine as a light yellow liquid (0.4 g, 93% yield).
Example 4
Preparation of 2-isopropyl-5-vinyl-pyridine
The title compound was prepared by following general procedure 2. 5-Bromo-2-isopropyl-pyridine (0.75 g, 3.7 mmol) was dissolved in DMF:THF (3:1, 6 mL). Tributylvinyltin (1.2 mL, 4.12 mmol) and Pd(PPh3)4 (0.070 g, 0.06 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (90% DCM-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-isopropyl-5-vinylpyridine as a light yellow liquid (0.5 g, 90% yield).
Example 5
Preparation of 2-trifluoromethyl-5-vinyl-pyridine
The title compound was prepared by following general procedure 2. 5-Bromo-2-trifluoromethylpyridine (2.0 g, 8.8 mmol) was dissolved in DMF:THF (3:1, 12 mL). Tributylvinyltin (3.0 g, 9.68 mmol) and Pd(PPh3)4 (0.135 g, 0.11 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (120 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-(trifluoromethyl)-5-vinylpyridine as a light yellow oil (0.8 g, 52% yield).
Example 6
Preparation of methyl 5-vinylpyridine-2-carboxylate
The title compound was prepared by following general procedure 2. Methyl 5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mL dioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solution at 25° C., followed by addition of dichlorobis(triphenylphosphine)palladium (1.5 g, mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. and then heated at 100° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-50% ethyl acetate-hexane gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 2 g of methyl 5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40% Ethyl acetate:Hexane.
Example 7
Preparation of 2-methyl-5-vinyl-pyridine
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyridine (5 g, 29.0 mmol) was dissolved in DMF:THF (3:1, 35 mL): tributylvinyltin (10.2 g, 31.9 mmol) and Pd(PPh3)4 (0.44 g, 0.432 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (350 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (6% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyridine as a light yellow oil (1.6 g, 47% yield).
Example 8
Preparation of 3-vinyl pyridine
The title compound was prepared by following general procedure 2. 3-Bromo pyridine (3.0 g, 18.9 mmol) was dissolved in DMF (9 mL), tributylvinyltin (6.62 g, 20.8 mmol) and Pd(PPh3)4 (0.326 g, 0.282 mol) was added to this solution at RT under nitrogen and heated at 80° C. for 3 h. The reaction mixture was cooled to RT, diluted with water (90 mL) and extracted with DCM (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (5% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide the desired compound as a light yellow liquid (0.62 g, 30% yield).
Example 9
Preparation of 2-methyl-5-vinyl-pyrimidine
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl-pyrimidine (1.7 g, 9.87 mmol) was dissolved in DMF:THF (3:1 24 mL). Tributylvinyltin (3.2 mL, 10.8 mmol) and Pd(PPh3)4 (0.148 g, 0.128 mmol) was added to this solution at RT under nitrogen and was heated at 120° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (20% Ethyl acetate-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrimidine a as light yellow liquid (1.1 g, 91% yield).
Example 10
Preparation of 5-vinyl-pyrimidine
The title compound was prepared by following general procedure 2. 5-Bromo pyrimidine (0.5 g, 3.2 mmol) was dissolved in DMF (6 mL), to this solution, tributylvinyltin (1.15 g, 3.5 mmol) and Pd(PPh3)4 (0.06 g, 0.05 mmol) was added at RT under nitrogen and was heated at 100° C. for 1.5 h. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (4% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide 5-vinylpyrimidine as a light yellow liquid (0.32 g, 95% yield).
Example 11
Preparation of 2-methyl-5-vinyl-pyrazine
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyrazine (2.0 g, 11 mmol) was dissolved in DMF:THF (3:1, 24 mL). Tributylvinyltin (3.0 g, 12.6 mmol) and Pd(PPh3)4 (0.172 g, 0.143 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with water (240 mL) and extracted with ethyl acetate (3×150 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrazine as a light yellow oil (1.0 g, 71% yield).
Example 12
Preparation of 1-methyl-5-vinylpyridin-2(1H)-one
The title compound was prepared by following general procedure 2. To a solution of 5-bromo-1-methylpyridin-2(1H)-one (2 g, 10.63 mmol) in 20 mL of 1,4-dioxane, dichlorobis(triphenylphosphine)palladium(II) (0.834 g, 1.19 mmol) was added at RT and stirred at the same temperature for 5 min. Tributylvinyltin (3.46 mL, 1.19 mmol) was added slowly at RT and stirred at 100-105° C. for 2 h. The reaction was monitored by TLC and LCMS. After completion of the starting material, the solvent was evaporated and the residue purified by column chromatography using 60% ethyl acetate-hexane to afford 1.2 g of 1-methyl-5-vinylpyridin-2(1H)-one.
Example 13
Preparation of 2-propyl-5-vinyl-pyridine
The title compound was prepared by following general procedure 2. 5-Bromo-2-propyl-pyridine (0.5 g, 2.5 mmol) was dissolved in DMF:THF (3:1, 8 mL). To this solution, tributylvinyltin (1.3 mL, 3.7 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol) was added at RT under nitrogen and was heated at 100° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (80 mL) and extracted with DCM (3×100 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (3% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5.0 cm, Height of silica—approx. 5 inch) to provide 2-propyl-5-vinylpyridine as a light yellow liquid (0.15 g, 41% yield).
Example 14
Preparation of 5-vinylpicolinic acid
The title compound was prepared by following general procedure 2. To a solution of 5-bromo pyridine-2-carboxylic acid (5 g, 24.75 mmol) in 50 mL of 1,4-dioxan, dichlorobis(triphenylphosphine)palladium(II) (2.08 g, 2.96 mmol) was added at RT and stirred at RT for 5 min. Tributylvinyltin (11.7 g, 36.9 mmol) was added slowly at RT and stirred at 100° C. for 3 h. The reaction mixture was monitored by TLC and LCMS. After completion of the starting material, evaporated the solvent below 40° C. and purified by column chromatography using ethyl acetate to afford the 5-vinylpyridine-2-carboxylic acid (3.5 g, 94.5%).
Example 15
Preparation of 2-methyl-5-(oxiran-2-yl)pyridine
The title compound was prepared by following general procedure 3. DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 equiv.) and heated to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 equiv.) was added and stirred for 10 min. and then a solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h, the product was detected by LCMS. The reaction mixture was poured into ice water and the product was extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to get the crude product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g crude).
Example 16
Preparation of 2-(4-fluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2 mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl)ethanone (2 g, 14.47 mmol, 1 equiv.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The progress of the reaction was checked by TLC and the reaction mixture was poured in 100 mL water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×150 mL), followed by brine. The organic layer was dried over sodium sulfate and evaporated to dryness to yield a brown oil (2.2 g). 1H NMR (d6-acetone) was consistent with the structure. Product Rf 0.8 (ethyl acetate:hexane 10:90)
Example 17
Preparation of 2-p-tolyloxirane
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (10.28 g, 50.37 mmol, 1.2 equiv.) in DMSO (70 mL) was added sodium hydride 60% dispersion in oil (2.82 g, 70.5 mmol, 1.7 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 4-methylbenzaldehyde (5.0 g, 42.0 mmol, 1 equiv.) in DMSO (25 mL) was added to the reaction mixture dropwise over 20 min. It was stirred at RT for 4 h. The reaction mixture was checked by TLC and the reaction mixture was poured in water (150 mL) and extracted with ethyl acetate. The combined organic extract was washed with water and brine and dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-p-tolyloxirane (5.2 g).
Example 18
Preparation of 3-(oxiran-2-yl)pyridine
The title compound was prepared by following general procedure 3. Sodium hydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 equiv.) was taken into DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added at the same temperature and heated for 10 min. The reaction mixture was cooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1 equiv.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1 equiv.) and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 3-(oxiran-2-yl)pyridine (1 g).
Example 19
Preparation of 2-(2,4,6-trifluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After completion of this addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted with diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 20
Preparation of 2-(2,4-dichlorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the reaction mixture was stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 21
Preparation of 2-(2,4-difluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 22
Preparation of 2-(3,4-dichlorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 23
Preparation of 2-(3,4-difluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 24
Preparation of 2-(3-chloro-4-fluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 25
Preparation of 2-(3-fluoro-4-methoxyphenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS, the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 26
Preparation of 2-(3-fluoro-4-methoxyphenyl)oxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 27
Preparation of 2-(4-chloro-3-fluorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 28
Preparation of 2-(4-chlorophenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 29
Preparation of 2-(4-fluorophenyl)-2,3-dimethyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Triethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 30
Preparation of 2-(4-methoxyphenyl)-2-methyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 31
Preparation of 2-(trifluoromethyl)-2-(4-fluorophenyl)oxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 32
Preparation of 2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 33
Preparation of 2-(trifluoromethyl)-5-(oxiran-2-yl)pyridine
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 34
Preparation of 2-cyclopropyl-2-(4-fluorophenyl)oxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of cyclopropyl (4-fluorophenyl)methanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 35
Preparation of 2-ethyl-2-(4-fluorophenyl)oxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl)propan-1-one (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 36
Preparation of 2-methyl-2-phenyloxirane
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 37
Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyridine
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 38
Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyrimidine
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Example 39
Preparation of 9-chloro-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 1)
The title compound was prepared by following general procedure 4. A mixture of 9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (117 mg, 0.5 mmol) 2-trifluoromethyl-5-vinylpyridine (95 mg, 0.55 mmol, 1.1 equiv.) and KOH (crushed, 98 mg, 1.75 mmol, 3.5 equiv.) in NMP (0.3 mL) was stirred and heated at 50° C. for 3 h. The reaction mixture was cooled to RT and diluted by adding ice and satd. aqueous NaCl. The aqueous was extracted with ethyl acetate and organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude product as an orange oil (153 mg). The crude product was purified by flash chromatography on silica gel (6 g, 40-63 micron, 230-400 mesh) eluting with ethyl acetate followed by ethyl acetate: ethanol: aqueous ammonia (90:10:1) to obtain 80 mg (39% yield) of 9-chloro-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole as free base. The free base was converted into its HCl salt by treatment with HCl-ether.
Example 40
Preparation of 9-chloro-3-methyl-6-(2-(5-methylpyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 3)
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.85 mmol), tetra n-butyl ammonium chloride (11 mg, 0.043 mmol), 3-methyl-5-vinylpyridine (121 mg, 1.02 mmol) were taken into 50% NaOH (6 mL) and the reaction mixture was heated overnight at 90° C. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with ethyl acetate and water, the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by preparative TLC to obtain 9 mg of 9-chloro-3-methyl-6-(2-(5-methylpyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, isolated as its oxalate salt. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 8.40 (s, 1H), 8.0 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.40 (t, 2H), 3.70 (t, 2H), 3.30 (s, 3H), 3.20 (m, 5H), 3.0 (s, 3H), 2.38 (s, 3H).
Example 41
Preparation of 6-(2-(5-chloropyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 4)
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol), 3-chloro-5-vinylpyridine (77 mg, 0.55 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction mixture was extracted with ethyl acetate and organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 150 mg of 6-(2-(5-chloropyridin-3-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 42
Preparation of 9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(pyridin-4-yl)ethyl)azepino[4,5-b]indole (Compound No. 5)
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol), tetra n-butyl ammonium chloride (6 mg, 0.025 mmol), 4-vinylpyridine (53 mg, 0.51 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with ethyl acetate and water, the organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 9-chloro-3-methyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 43
Preparation of 1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-(2-(pyridin-4-yl)ethyl)azepino[4,5-b]indole (Compound No. 6)
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol), 4-vinylpyridine (58 mg, 0.55 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction mixture was extracted with ethyl acetate and organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 100 mg of 3,9-dimethyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 44
Preparation of 9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(pyridin-2-yl)ethyl)azepino[4,5-b]indole (Compound No. 8)
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.6 mmol) in 50% aq. NaOH solution (7 mL), tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) was added followed by 2-vinylpyridine (74 mg, 0.7 mmol) The reaction mixture was heated at 80° C. for 14 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 80 mg of 9-chloro-3-methyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Example 45
Preparation of 1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)azepino[4,5-b]indole (Compound No. 9)
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.7 mmol) in 50% aq. NaOH solution (7 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 2-vinylpyridine (80 mg, 0.77 mmol) was added and the reaction mixture was heated at 80° C. for 14 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 80 mg of 3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Example 46
Preparation of 9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 10)
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol) in 50% aq. NaOH solution (5 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 3-chloro-5-vinylpyridine (65 mg, 0.47 mmol) was added. The reaction mixture was heated at 60° C. for 8 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 5 mg of 9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Example 47
Preparation of 5-(2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethyl)pyridine-2-carboxylic acid (Compound No. 11)
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.93 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butyl ammonium chloride (12 mg, 0.046 mmol) followed by 5-vinylpicolinic acid (153 mg, 1.0 mmol). The reaction mixture was heated at 90° C. for overnight, and the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 7 mg of 5-(2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinic acid as the TFA salt.
Example 48
Preparation of 6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 20)
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.69 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butyl ammonium chloride (9 mg, 0.034 mmol) followed by 2-(trifluoromethyl)-5-vinylpyridine (133 mg, 0.76 mmol). The reaction mixture was heated at 120° C. for 8 h and the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 15 mg of 3,9-dimethyl-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Example 49
Preparation of 5-(2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)ethyl)pyridine-2-carboxylic acid (Compound No. 21)
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.85 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butyl ammonium chloride (11 mg, 0.042 mmol) followed by 5-vinylpicolinic acid (140 mg, 0.94 mmol). The reaction mixture was heated at 90° C. for overnight and was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 8 mg of 5-(2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinic acid as the TFA salt.
Example 50
Preparation of 6-(4-chlorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 28)
The title compound was prepared by following general procedure 4. 6-(4-Chlorophenethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.214 g, 1 mmol) along with tetrabutylammonium chloride (0.138 g, 0.0005 mmol) were taken into 50% aq. NaOH solution (5 mL) and stirred for 5 min. at RT, 1-(2-bromoethyl)-4-chlorobenzene (0.219 g, 1 mmol) was added and stirred for 5 min. at RT and then the reaction mixture was heated at 110° C. for overnight. The product detected by LCMS, extracted in ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by reverse phase chromatography to get the pure compound 6-(4-chlorophenethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Example 51
Preparation of 6-(2-chlorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 29)
The title compound was prepared by following general procedure 4. 9-Chloro-6-(2-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.234 g, 1 mmol) along with tetrabutylammonium chloride (0.026 g, 0.094 mmol) were taken into 50% aq. NaOH solution (4 mL) and stirred for 15 min. at RT, 1-(2-bromoethyl)-2-chlorobenzene (0.878 g, 4 mmol) was added and stirred for 10 min. at RT and then the reaction mixture was heated at 100° C. for overnight. Product detected by LCMS. The product was extracted in ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by reverse phase chromatography to get pure compound 9-chloro-6-(2-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydro azepino[4,5-b]indole as the TFA salt (70 mg)
Example 52
Preparation of 6-(4-chlorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 30)
The title compound was prepared by following general procedure 4. 9-Chloro-6-(4-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.234 g, 1 mmol) along with tetrabutylammonium chloride (0.026 g, 0.094 mmol) were taken into 50% aq. NaOH solution (4 mL) and stirred for 15 m in. at RT, 1-(2-bromoethyl)-4-chlorobenzene (0.878 g, 4 mmol) was added and stirred for 10 min. at RT and the reaction mixture was heated at 100° C. for overnight. The product detected by LCMS, extracted in ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by reverse phase chromatography to get pure compound 9-chloro-6-(4-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydro azepino[4,5-b]indole as the TFA salt (50 mg)
Example 53
Preparation of 9-chloro-3-methyl-6-(4-methylphenethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 46)
The title compound was prepared by following general procedure 4. TBACl (138 mg, 0.5 mmol) was taken into 50% NaOH (5 mL), and to it was added 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepinol[4,5-b]indole (234 mg, 1.0 mmol), stirred for 5 min. at RT, and added 1-(2-bromoethyl)-4-methylbenzene (199 mg, 1.0 mmol), the reaction was then stirred at 110° C. for 12 h. The completion of reaction was checked by LCMS. Water was added and the mixture extracted by DCM which was dried over sodium sulfate and concentrated under vacuum. The crude so obtained was purified by reverse phase chromatography to get pure product.
Example 54
Preparation of 9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-phenethylazepino[4,5-b]indole (Compound No. 56)
The title compound was prepared by following general procedure 4. TBACl (59 mg, 0.213 mmol) was taken into 50% NaOH (5 mL), to it added 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepinol[4,5-b]indole (100 mg, 0.426 mmol), stirred for 5 min. at RT and added (2-bromoethyl)benzene (78 mg, 0.426 mmol) the reaction was stirred at 100° C. for 12 h. The completion of reaction was checked by LCMS. Water was added and the mixture extracted with DCM which was dried over sodium sulfate and concentrated under vacuum. The crude so obtained was purified by reverse phase chromatography. The pure compound so obtained was made free base and converted to oxalate salt in THF.
Example 55
Preparation of 6-(2-fluorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 61)
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and then 1-(2-bromoethyl)-2-fluorobenzene (203 mg, 1 mmol) in DMF. The reaction mixture was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel 100-200 mesh) (gradient 5% MeOH:DCM). The pure product was converted to its oxalate salt using oxalic acid and THF.
Example 56
Preparation of 1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-phenethylazepino[4,5-b]indole (Compound No. 62)
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and (2-bromoethyl)benzene (185 mg, 1 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h. The reaction was monitored by LCMS. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude so obtained was purified by column chromatography (silica gel 100-200 mesh) (gradient 5% MeOH:DCM). The pure product was converted to oxalate salt using oxalic acid and THF.
Example 57
Preparation of 6-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 63)
The title compound was prepared by following general procedure 4. Tetrabutylammonium chloride (138 mg, 0.0005 mmol) was taken into 50% NaOH (10 mL) 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was added and stirred for 5 min. at RT. 1-(2-Bromoethyl)-2-fluorobenzene (203 mg, 1 mmol) was added, the reaction was stirred at 100° C. for 12 h. The completion of reaction was checked by LCMS. Water was added to the reaction mixture and extracted with DCM which was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford the title compound.
Example 58
Preparation of 6-(2-chlorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 69)
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-praline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol), 1-(2-bromoethyl)-2-chlorobenzene (219 mg, 1.0 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford 50 mg of the title compound (10.7%).
Example 59
Preparation of N-cyclohexyl-3-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-methylpropanamide (Compound No. 81)
The title compound was prepared by following general procedure 8. Sodium hydride (0.027 g, 0.69 mmol) washed with hexane for removal of oil and dried under vacuum. Then the sodium hydride was taken into THF. To this solution 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of N-cyclohexyl-N-methylacrylamide (0.115 g, 0.93 mmol) in THF was added dropwise into the reaction mixture. The reaction mixture was stirred at RT for 2 h and monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-water. The crude compound was purified by preparative TLC. The pure compound was stirred in ethanolic HCl to give 6 mg HCl salt of N-cyclohexyl-3-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-methylpropanamide.
Example 60
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol (Compound No. 7)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol) was dissolved in DMF (2 mL). To a solution of sodium hydride (50%) (100 mg, 2.2 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-methyl-5-(oxiran-2-yl)pyridine (270 mg, 2 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for overnight at RT. The product was detected by LCMS, the reaction mixture was quenched with methanol and concentrated to dryness. Water was added to the residue and product was extracted in ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol as the TFA salt (195 mg, 40.37%). 1HNMR (DMSO-d6, TFA salt) δ (ppm): 8.40 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.0 (m, 1H), 5.80 (m, 1H), 4.90 (m, 1H), 4.30 (m, 1H), 3.60 (m, 4H), 3.20 (m, 4H), 3.0 (m, 4H), 2.80 (s, 3H).
Example 61
Preparation of 1-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol (Compound No. 12)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (214 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol) as the TFA salt.
Example 62
Preparation of 1-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol (Compound No. 13)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (194 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol) as the TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.40 (s, 1H), 7.30-7.18 (m, 3H), 7.0-6.80 (m, 3H), 4.40-4.25 (d, 2H), 4.25-4.15 (d, 2H), 3.40-3.20 (d, 2H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 1.50 (s, 3H).
Example 63
Preparation of 2-(4-fluorophenyl)-1-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)propan-2-ol (Compound No. 14)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (212 mg, 1.39 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography using 10% methanol-DCM. The freebase (30 mg, 0.082 mmol) was dissolved in THF (1.0 mL) and oxalic acid (10 mg, 0.082 mmol) in THF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. and the formed solid was filtered, washed with ether and dried to afford the product as oxalate salt (15 mg, brown solid).
Example 64
Preparation of 2-(4-chlorophenyl)-1-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)propan-2-ol (Compound No. 15)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (235 mg, 1.4 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography using 10% methanol-DCM. The freebase (30 mg, 0.078 mmol) was dissolved in THF (1.0 mL) and oxalic acid (9.8 mg, 0.078 mmol) in THF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. and the formed solid was filtered, washed with ether and dried to afford product as oxalate salt.
Example 65
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-chlorophenyl)ethanol (Compound No. 16)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (153 mg, 6.37 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.5 g, 2.13 mmol) was added and stirred at RT for 10 min. 2-(4-Chlorophenyl)oxirane (493 mg, 3.19 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-chlorophenyl)ethanol as the TFA salt (110 mg).
Example 66
Preparation of 1-(4-chlorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 17)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (167 mg, 6.99 mmol) in DMF (5 mL), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.5 g, 2.33 mmol) was added and stirred at RT for 10 min. 2-(4-Chlorophenyl)oxirane (541 mg, 3.504 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 1-(4-chlorophenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol as the TFA salt (180 mg).
Example 67
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol (Compound No. 18)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (92 mg, 3.83 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.27 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (232 mg, 1.92 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 250 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Example 68
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol (Compound No. 19)
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (94 mg, 3.92 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.40 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (254 mg, 1.54 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 200 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Example 69
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol (Compound No. 23)
The title compound was prepared by following general procedure 5. 2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol) was taken into DMF (2 mL). To a solution of sodium hydride (50%) (100 mg, 2.2 mmol) was in portions at RT and stirred at RT for 10 min. A solution of 2-methyl-5-(oxiran-2-yl)pyridine (270 mg, 2 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for overnight at RT. The product was detected by LCMS, the reaction mixture was quenched with methanol and concentrated to dryness. Water was added to the residue and product was extracted in ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol as the TFA salt (10 mg).
Example 70
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol (Compound No. 24)
The title compound was prepared by following general procedure 5. (2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) in 6.0 mL DMF, sodium hydride (92 mg, 3.834 mmol) was added slowly portionwise at RT, followed by the addition of 2-phenyloxirane (230 mg, 1.917 mmol) and stirred at RT for 14 h. The reaction mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to obtain 150 mg of product as the TFA salt.
Example 71
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol (Compound No. 25)
The title compound was prepared by following general procedure 5. (2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol). To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) in 10 mL DMF, sodium hydride (100 mg, 4.203 mmol) was added slowly portionwise at RT, followed by the addition of 2-phenyloxirane (252 mg, 2.10 mmol) and stirred at RT for 14 h. LCMS shows the formation of product. The reaction mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to obtain 250 mg of product as the TFA salt.
Example 72
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol (Compound No. 26)
The title compound was prepared by following general procedure 5. (2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol). To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) in 10 mL DMF, sodium hydride (92 mg, 3.834 mmol) was added slowly portionwise at RT, followed by the addition of 2-p-tolyloxirane (256 mg, 1.917 mmol) and stirred at RT for 14 h. The reaction mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to obtain 230 mg of product as the TFA salt.
Example 73
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol (Compound No. 27)
The title compound was prepared by following general procedure 5. (2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol). To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) in 10 mL DMF, sodium hydride (100 mg, 4.203 mmol) was added slowly portionwise at RT, followed by the addition of 2-p-tolyloxirane (281 mg, 2.10 mmol) and stirred at RT for 14 h. LCMS shows the formation of product. The reaction mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to obtain 85 mg of (Yield: 17.3.0%) title compound as the TFA salt.
Example 74
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol (Compound No. 40)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(2-fluorophenyl)oxirane (264 mg, 1.92 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The product was detected by LCMS, the reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol as the TFA salt (240 mg). 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.70-7.50 (m, 2H), 7.40-7.00 (m, 5H), 5.10-5.00 (t, 1H), 4.40-4.20 (m, 4H), 3.40-3.10 (m, 6H), 2.90 (s, 3H).
Example 75
Preparation of 1-(2-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 41)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(2-fluorophenyl)oxirane (290 mg, 2.11 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol as the TFA salt (260 mg). 1HNMR (DMSO-d6, TFA salt) δ (ppm): 7.60 (m, 1H), 7.30 (m, 5H), 6.99 (m, 1H), 5.80 (m, 1H), 5.05 (m, 1H), 4.30 (m, 2H), 3.80 (m, 4H), 3.35 (m, 4H), 3.0 (s, 3H), 2.40 (s, 3H).
Example 76
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol (Compound No. 42)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 4-(oxiran-2-yl)pyridine (232 mg, 1.9 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol as the TFA salt (230 mg). 1HNMR (DMSO-d6, TFA salt) δ (ppm): 8.65 (m, 2H), 7.80-7.45 (m, 3H), 7.40 (m, 1H), 7.0 (m, 1H), 6.0 (m, 1H), 4.95 (m, 1H), 4.40 (m, 2H), 3.40 (m, 3H), 3.20 (m, 4H), 2.92 (s, 3H).
Example 77
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol (Compound No. 43)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 4-(oxiran-2-yl)pyridine (254 mg, 2.11 mmol) in DMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol as the TFA salt (250 mg).
Example 78
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol (Compound No. 47)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(4-methoxyphenyl)oxirane (287 mg, 1.92 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol as the TFA salt (150 mg).
Example 79
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol (Compound No. 48)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(4-methoxyphenyl)oxirane (315 mg, 2.11 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LC MS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol as the TFA salt (210 mg).
Example 80
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol (Compound No. 49)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(2-fluoro-4-methoxyphenyl)oxirane (322 mg, 1.92 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxy phenyl)ethanol as the TFA salt (230 mg).
Example 81
Preparation of 1-(2-fluoro-4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 50)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (100 mg, 4.2 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(2-fluoro-4-methoxyphenyl)oxirane (353 mg, 2.10 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol as the TFA salt (300 mg).
Example 82
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol (Compound No. 51)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 5 min. A solution of 2-(4-fluorophenyl)oxirane (264 mg, 1.92 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol as the TFA salt (90 mg).
Example 83
Preparation of 1-(4-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 52)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (100 mg, 4.2 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(4-fluorophenyl)oxirane (290 mg, 2.10 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol as the TFA salt (150 mg).
Example 84
Preparation of Cyclopentyl-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetate (Compound No. 55)
The title compound was prepared by following general procedure 9. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) was added to the solution and stirred for 10 min. at RT cyclopentyl 2-chloroacetate (90 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. To obtain 20 mg of cyclopentyl 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate. Then purified compound was taken into ethanol in HCl to gives HCl salt of desired compound.
Example 85
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanol (Compound No. 58)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.13 mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%) (153 mg, 6.39 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3,4-difluorophenyl)oxirane (498 mg, 3.19 mmol) in DMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanol as the TFA salt (180 mg).
Example 86
Preparation of 1-(2,4-difluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 59)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(2,4-difluorophenyl)oxirane (546 mg, 3.50 mmol) in DMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by LCMS. The reaction mixture was quenched with ice water, extracted in ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol as the TFA salt (60 mg).
Example 87
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (Compound No. 67)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (6 mL). Sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3-fluoro-4-methoxyphenyl)oxirane (322 mg, 1.92 mmol) in DMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol as the TFA salt (200 mg).
Example 88
Preparation of 1-(3-fluoro-4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 68)
The title compound was prepared by following general procedure 5. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40 mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%) (100 mg, 4.20 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3-fluoro-4-methoxyphenyl)oxirane (353 mg, 2.10 mmol) in DMF (4 mL) was added dropwise and stirred for 14 h at RT. The reaction was monitored by TLC and LCM S. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol as the TFA salt (250 mg).
Example 89
Preparation of Benzyl-2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)acetate (Compound No. 75)
The title compound was prepared by following general procedure 9. Preparation of benzyl 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) was added and stirred for 10 min. at RT. Benzyl 2-chloroacetate (95 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure, to afford 90 mg of benzyl 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 90
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol (Compound No. 77)
The title compound was prepared by following general procedure 5. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.27 mmol) was taken into DMF (6 mL). Sodium hydride (50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3,4-dimethoxyphenyl)oxirane (345 mg, 1.92 mmol) in DMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get pure product 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol as the TFA salt (8 mg).
Example 91
Preparation of 9-chloro-6-((E)-2-(4-fluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 2 and Compound No. 82)
The title compound was prepared by following general procedure 6. 1-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol (100 mg, 0.259 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 3 h. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 12 mg of product as the TFA salt along with 9-chloro-6-(2-(4-fluorophenyl)allyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole. Compound No. 82: 1H NMR (CDCl3, freebase) δ (ppm): 7.50-7.30 (m, 3H), 7.20-7.00 (m, 4H), 7.30-7.20 (d, 1H), 5.00-4.90 (t, 2H), 4.40-4.30 (d, 1H), 3.10-2.90 (m, 8H), 2.60 (s, 3H).
Example 92
Preparation of 6-((E)-2-(4-chlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 33)
The title compound was prepared by following general procedure 6. 2-(4-Chlorophenyl)-1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propan-2-ol (100 mg, 0.261 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 10 mg of product as the TFA salt along with 6-(2-(4-chlorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Example 93
Preparation of 6-((E)-2-(4-fluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 34)
The title compound was prepared by following general procedure 6. 1-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol (100 mg, 0.273 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 2 h. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 10 mg of product as the TFA salt along with 6-(2-(4-fluorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Example 94
Preparation of 9-chloro-6-((E)-2-(4-chlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 36 and Compound No. 35)
The title compound was prepared by following general procedure 6. 1-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chloro phenyl)propan-2-ol (100 mg, 0.248 mmol) was taken into 2.0 mL of 25% H2SO4 in water and stirred at 90° C. for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to obtain the title compound as the TFA salt along with 9-chloro-6-(2-(4-chlorophenyl)allyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Example 95
Preparation of 6-(4-methoxystyryl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 78)
The title compound was prepared by following general procedure 6. To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol (100 mg, 0.25 mmol) in DCM (2 mL), triethylamine (0.053 mL, 0.38 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.02 mL, 0.27 mmol) was added slowly at 0° C. and stirred at the same temperature for 1 h and stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography. Pure product was taken into NMP (2.0 mL), KOH powder (72 mg, 1.2 mmol) was added at RT and heated at 80° C. for 24 h. The product was detected by LCMS, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and crude product was purified by reverse phase chromatography to get 6 mg of pure product as the TFA salt.
Example 96
Preparation of N-cyclohexyl-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetamide (Compound No. 22)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.045 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) was added to the solution and stirred for 10 min. at RT. 2-chloro-N-cyclohexylacetamide (98 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. And purified by column chromatography and then oxalate salt was made by using oxalic acid (35 mg, 0.46 mmol) to obtain 100 mg of N-cyclohexyl-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide as the oxalate salt.
Example 97
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide (Compound No. 31)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) was added to the solution and stirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (65 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then the residue was extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 98
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone (Compound No. 32)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.47 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone (91 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 14 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 99
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide (Compound No. 37)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (96 mg, 0.53 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure, to obtain 20 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 100
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone (Compound No. 38)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (91 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. To obtain 4 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 101
Preparation of N-(4-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetamide (Compound No. 44)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (105 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 104 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 102
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone (Compound No. 45)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-(pyrrolidin-1-yl)ethanone (82 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 4 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 103
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone (Compound No. 53)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-chloro-1-(pyrrolidin-1-yl)ethanone (75 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 15 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 104
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide (Compound No. 54)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (76 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 7 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 105
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone (Compound No. 57)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone (83 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 6 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 106
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone (Compound No. 60)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (84 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 21 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 107
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone (Compound No. 72)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.85 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-1-(piperazin-1-yl)ethanone (0.135 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to gives 35 mg, and then the compound was stirred in ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone.
Example 108
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide (Compound No. 73)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) was added to the solution and stirred for 10 min. at RT. 2-Chloro-N-phenylacetamide (87 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobil e Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 109
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-cyclohexyl-N-methylacetamide (Compound No. 74)
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-cyclohexyl-N-methylacetamide (98 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 56 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-cyclohexyl-N-methylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Example 110
Preparation of 2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone (Compound No. 76)
The title compound was prepared by following general procedure 7. Sodium hydride (34 mg, 0.43 mmol) washed with hexane for removal of oil and dried under vacuum and taken in THF.
To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Example 111
Preparation of 2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide (Compound No. 79)
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) was added to the solution and stirred for 10 min. at RT. 2-Chloro-N-phenylacetamide (95 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to obtain 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide as the HCl salt using ethanolic HCl (29 mg).
The compounds prepared according to the Examples are further detailed in Table 3.







TABLE 3







Synthetic Data















FW




Compound
Salt
MW
(Salt
NMR


No.
Type
Free Base
Included)
Solvent
NMR_DATA















1
DiHCL
407.87
480.78
DMSO
11.0 (bs, 1H), 8.5 (s, 1H), 7.8 (d, 1H),







7.7 (d, 1H), 7.5 (s, 1H), 7.4 (d, 1H), 7.0 (d, 1H),







4.5 (t, 2H), 3.6 (bs, 2H), 3.3-3.0 (m, 8H),







2.9 (s, 3H),


4
TFA
353.90
467.91
CD3OD
10.13 (bs, 1H), 9.10 (bs, 1H), 8.42 (s, 1H),







8.22 (s, 1H), 7.70 (s, 1H), 7.26 (d, 1H),







7.10 (s, 1H), 6.90 (d, 1H), 4.17-4.22 (m, 2H),







3.10-3.21 (m, 5H), 2.83-3.07 (m, 8H),







2.40 (t, 3H)


5
TFA
339.87
453.89
CD3OD
10.0 (bs, 1H), 8.55 (d, 2H2H), 7.57 (d, 1H),







7.40-7.45 (m, 3H), 7.07 (dd, 1H), 4.50 (t,







2H), 3.50-3.63 (m, 4H), 3.15-3.23 (m, 6H),







2.90 (t, 3H).


6
TFA
319.45
433.47
CD3OD
10.1 (bs, 1H), 8.60 (d, 2H), 7.50 (d, 2H),







7.11-7.20 (m, 2H), 6.90 (d, 1H), 4.42 (t,







2H), 3.10-3.25 (m, 6H), 3.05 (t, 4H), 2.95 (s,







3H), 2.45 (s, 3H).


8
TFA
339.87
453.89
DMSO
8.60-8.56 (d, 1H), 8.20-8.10 (t, 1H),







7.70-7.60 (t, 1H), 7.60-7.50 (d, 1H), 7.40 (s, 1H),







7.20-7.10 (d, 1H), 7.00-6.90 (d, 1H),







4.50-4.40 (t, 2H), 3.60-3.30 (t, 4H), 3.30-3.10 (m,







6H), 2.90 (s, 3H).


9
TFA
319.45
433.47
DMSO
8.60-8.50 (d, 1H), 8.10-8.00 (t, 1H),







7.60-7.50 (t, 1H), 7.50-7.40 (d, 1H), 7.20 (s, 1H),







7.18-7.11 (d, 1H), 6.90-6.80 (d, 1H),







4.50-4.40 (t, 2H), 3.60-3.50 (t, 2H), 3.30-3.10 (m,







8H), 2.90 (s, 3H), 2.30 (s, 3H).


10
TFA
374.32
488.33
DMSO
8.54-8.45 (m, 1H), 8.30-8.25 (s, 1H),







7.75-7.70 (d, 1H), 7.60-7.55 (d, 1H),







7.50-7.45 (d, 1H), 7.05 (d, 1H), 4.5-4.40 (m, 2H),







3.70-3.55 (m, 2H), 3.30-3.10 (m, 6H),







3.05-2.85 (m, 5H).


11
TFA
363.46
477.48
DMSO
2.35-2.40 (s, 3H), 2.65-2.80 (m, 2H),







2.85-2.95 (m, 5H), 3.02-3.20 (m, 6H),







4.35-4.50 (t, 2H), 6.90-6.95 (d, 1H), 7.25-7.35 (m,







2H), 7.65-7.70 (d, 1H), 7.90-7.95 (d, 1H),







8.32-8.35 (s, 1H), 9.75-9.90 (m, 1H).


12
TFA
403.36
517.37
DMSO
7.50-7.20 (m, 6H), 7.00-6.90 (t, 1H),







4.30-4.20 (d, 2H), 4.20-4.10 (d, 2H),







3.60-3.40 (m, 2H), 3.30-3.00 (m, 4H), 2.90 (s, 3H),







1.50-1.40 (d, 3H).


14
OXALATE
366.48
456.51
DMSO
7.50-7.40 (t, 2H), 7.30-7.00 (m, 4H),







6.90-6.80 (d, 1H), 4.30-20 (d, 2H), 4.20-4.10 (d,







2H), 3.20-3.00 (m, 6H), 2.90 (s, 3H),







2.30 (s, 3H), 1.40 (t, 3H).


15
OXALATE
382.94
472.96
DMSO
7.50-7.40 (d, 2H), 7.40-7.20 (m, 3H),







6.90-6.70 (dd, 2H), 4.30-4.20 (d, 2H),







4.20-4.00 (d, 2H), 3.20-3.00 (m, 6H), 2.90 (s, 3H),







2.30 (s, 3H), 1.40 (s, 3H).


16
TFA
389.33
503.34
DMSO
7.50-7.40 (t, 1H), 7.38-7.18 (m, 5H),







7.10-7.00 (d, 1H), 4.80-4.70 (d, 2H),







4.30-4.20 (d, 2H), 3.60-3.50 (m, 4H), 3.20-3.00 (m,







2H), 2.90 (s, 3H)..


17
TFA
368.91
482.92
DMSO
7.40-7.20 (m, 6H), 6.98-6.80 (d, 1H),







4.90-4.70 (dd, 2H), 4.30-4.10 (t, 2H),







3.60-3.40 (m, 2H), 3.30-3.00 (m, 4H), 2.90 (s, 3H),







2.30 (s, 3H).


18
TFA
355.87
469.88
DMSO
8.70-8.50 (dd, 2H), 8.30-8.20 (d, 1H),







7.80-7.70 (m, 1H), 7.50-7.40 (t, 1H),







7.30-7.20 (m, 1H), 7.10-6.90 (t, 1H), 5.10-5.00 (m,







2H), 4.20-4.10 (t, 2H), 3.70-3.58 (m, 2H),







3.40-3.20 (m, 4H), 2.90 (s, 3H).


19
TFA
335.45
449.47
DMSO
8.80-8.60 (dd, 2H), 8.30-8.20 (d, 1H),







7.90-7.70 (m, 1H), 7.10-7.00 (t, 1H),







7.00-6.90 (m, 1H), 6.90-6.80 (t, 1H), 5.10-5.00 (m,







2H), 4.40-4.30 (d, 2H), 3.70-3.50 (m, 2H),







3.40-3.00 (m, 4H), 2.90 (s, 3H), 2.25 (s,







3H).


20
TFA
387.45
501.46
DMSO
10.1-9.9 (m, 1H), 8.45 (s, 1H), 7.95-7.75 (m,







2H), 7.30-7.20 (m, 2H), 6.95-6.85 (d, 1H),







4.50-4.35 (t, 2H), 3.23-3.00 (m, 8H),







2.95-2.85 (m, 6H), 2.35 (s, 3H).


21
TFA
383.88
497.89
DMSO
10.05-9.95 (m, 1H), 8.35 (s, 1H),







7.9-7.85 (d, 1H), 7.75-7.65 (d, 1H), 7.60-7.55 (s, 1H),







7.50-7.40 (d, 1H), 7.10-7.05 (d, 1H),







4.55-4.40 (m, 2H), 3.25-2.80 (m, 13H).


22
OXALATE
353.51
443.54
DMSO
−10.9 (s, 1H), 8.62 (d, 1H), 7.19-7.22 (m,







2H), 6.90 (d, 1H), 4.25 (s, 2H), 3.6-4.0 (m,







6H), 3.2-3.4 (m, 6H), 2.4 (s, 3H),







1.5-1.9 (m, 5H), 1.1-1.4 (m, 5H).


23
TFA
349.48
463.49
DMSO
10.8 (s, 1H) 8.97 (s, 1H) 7.90-7.84 (m, 1H)







7.43-7.37 (m, 1H), 7.25-7.15 (m, 1H),







6.70-6.10 (m, 2H), 5.42-5.38 (d, 1H),







4.10-3.70 (m, 6H) 3.20-3.0 (m, 4H) 2.70 (S, 3H)







2.50 (s, 3H) 2.38 (s, 3H).


24
TFA
354.88
468.90
DMSO
7.80-7.70 (t, 1H), 7.70-7.60 (t, 1H),







7.38-7.30 (m, 5H), 7.20-7.0 (d, 1H), 4.85-4.80 (m,







2H), 4.30-4.20 (d, 4H), 3.0-2.80 (m, 7H).


25
TFA
334.47
448.48
DMSO
7.40-7.25 (m, 6H), 6.95-6.85 (d, 2H),







4.80-4.75 (t, 2H), 4.35-4.25 (m, 4H),







3.0-2.80 (m, 7H), 2.35 (s, 3H).


26
TFA
368.91
482.92
DMSO
7.50-7.40 (m, 2H), 7.20-7.0 (m, 5H),







4.80-4.70 (d, 2H), 4.25-4.20 (t, 4H), 3.25-3.10 (m,







4H), 3.0-2.95 (s, 3H), 2.25 (s, 3H).


27
TFA
348.49
462.50
DMSO
7.40-7.20 (m, 5H), 7.0-6.90 (d, 2H),







4.82-4.70 (d, 2H), 4.30-4.10 (m, 4H),







3.15-2.95 (m, 4H),







2.95-2.90 (t, 3H), 2.40 (s, 3H), 2.30 (s, 3H).


28
TFA
352.91
466.92
CD3OD
1H NMR 7.40-7.10 (m, 3H), 7.10-7.00 (d, 2H),







6.90-6.80 (d, 2H), 4.40-4.30 (t, 2H),







3.20-3.10 (m, 8H), 3.10-3.00 (t, 2H), 3.00 (s, 3H),







2.40 (s, 3H)


29
TFA
373.33
487.34
CD3OD
7.60 (s, 1H), 7.45-7.38 (m, 2H),







7.32-7.05 (m, 4H), 4.42-4.37 (t, 2H), 3.70-3.37 (m,







4H), 3.30-3.0 (m, 6H), 2.90 (s, 3H)


30
TFA
373.33
487.34
CD3OD
7.58 (s, 1H), 7.50-7.45 (d, 1H),







7.35-7.25 (m, 2H), 7.16-7.06 (m, 3H), 4.41-4.36 (t,







2H), 3.72-3.50 (m, 4H), 3.30-3.0 (m, 6H)







2.90 (s, 3H).


31
TFA
333.86
447.88
DMSO
−11.23 (s, 1H), 8.53 (d, 1H), 7.52 (s, 1H,),







7.30 (d, 1H), 7.24 (d, 1H), 4.80 (d, 1H),







4.70 (d, 1H), 4.11-4.27 (m, 2H), 3.75-4.0 (m,







5H), 3.10-3.39 (m, 5H), 1.10 (d, 6H).


32
TFA
339.48
453.50
CD3OD
7.23 (s, 1H), 7.19 (d, 1H), 6.94 (d, 1H),







4.60 (s, 2H), 4.18-4.29 (m, 2H),







3.85-3.99 (m, 2H), 3.43-3.60 (m, 7H), 3.23-3.40 (m,







4H), 2.40 (s, 3H), 1.50-1.76 (m, 6H).







10.7 (bs, 1H), 7.20-7.24 (m, 2H), 6.90 (d, 1H),







5.20 (s, 2H), 3.46-3.63 (m, 4H),







3.30-3.40 (m, 2H), 3.09-3.13 (m, 4H), 2.92-3.02 (m,







2H), 2.87 (s, 3H), 2.31 (s, 3H),







1.50-1.62 (m, 4 H), 1.34-1.43 (m, 2H)..


33
TFA
364.92
478.93
DMSO
7.70-7.60 (d, 2H), 7.50-7.40 (d, 2H), 7.30 (s,







2H), 7.10-6.90 (m, 2H), 3.70-3.40 (m, 4H),







2.95 (s, 3H), 2.35 (s, 3H), 1.80-1.70 (m,







4H).


34
TFA
348.47
462.48
DMSO
7.70-7.60 (t, 2H0, 7.35-7.20 (m, 2H),







7.02-6.90 (m, 3H), 3.70-3.50 (m, 4H),







3.30-3.20 (m, 5H), 2.95 (s, 3H), 2.35 (s, 3H),







1.90-1.80 (t, 2H).


35
TFA
385.34
499.35
DMSO
7.60-7.50 (d, 4H), 7.40-7.30 (m, 2H),







7.15-7.00 (m, 1H), 5.30 (s, 1H), 5.10 (s, 1H),







3.70-3.50 (m, 4H), 3.35-3.20 (m, 4H),







2.95 (s, 3H).


36
TFA
385.34
499.35
DMSO
7.75-7.60 (m, 2H), 7.60 (s, 1H),







7.50-7.40 (d, 2H), 7.25-7.20 (m, 2H), 7.00 (s, 1H),







5.30-5.20 (m, 2H), 3.70-3.50 (m, 3H),







3.45-3.35 (m, 2H), 3.10 (s, 3H), 1.95-1.90 (t, 4H).


2
TFA
368.89
482.90
DMSO
7.75-7.60 (m, 2H), 7.65 (s, 1H), 7.35-7.20 (t,







4H), 6.95 (s, 1H), 3.75-3.40 (m, 4H),







3.30-3.20 (m, 5H), 2.95 (s, 2H), 1.95-1.90 (t, 2H).


37
TFA
385.87
499.89
DMSO
11.3 (s, 1H), 10.9 (s, 1H), 7.60-7.63 (m,







2H), 7.56 (s, 1H), 7.35 (d, 1H), 7.24 (t, 2H),







7.06 (d, 1H), 4.53 (s, 2H), 4.0-4.1 (m, 2H),







3.85-3.98 (m, 2H), 3.43 (s, 3H), 3.3-3.39 (m,







2H), 3.19-3.24 (m, 2H).


38
TFA
341.46
455.47
CD3OD
7.22 (s, 1H), 7.19 (d, 1H), 6.9 (d, 1H),







4.6 (s, 2H), 4.2-4.3 (m, 3H), 3.85-4.0 (m, 3H),







3.45-3.7 (m, 7H), 3.4-3.42 (m, 4H),







3.10-3.25 (m, 2H), 2.4 (s, 3H).


43
TFA
335.45
449.47
DMSO
DMSO 8.70-8.50 (d, 2H), 8.0-7.90 (m, 1H),







7.70-7.69 (d, 1H), 7.30-7.10 (m, 2H),







6.90-6.70 (m, 1H), 5.10-5.00 (t, 1H), 4.40-4.20 (t,







2H), 3.70-3.60 (m, 4H), 3.30-3.10 (m, 4H),







2.90 (s, 3H), 2.30 (s, 3H).


44
TFA
365.45
479.47
DMSO
−10.7-10.9 (m, 2H), 7.52-7.62 (m, 2H),







7.10-7.25 (m, 3H), 6.9 (d, 2H), 4.3-4.41 (m,







3H), 3.75-3.9 (m, 2H), 3.41 (s, 3H),







3.20-3.27 (m, 2H), 3.10-3.19 (m, 2H), 3.0 (s, 1H),







2.30 (s, 3H).


45
TFA
325.46
439.47
CD3OD
7.22 (s, 1H), 7.10 (d, 1H), 7.92 (d, 1H),







4.42-4.6 (m, 5H), 4.2-4.4 (m, 4H),







3.9-4.1 (m, 3H), 3.4-3.6 (m, 4H), 2.28-2.42 (m, 4H),







1.8-2.1 (m, 4H).


46
TFA
352.91
466.92
CD3OD
7.50 (s, 1H), 7.40-7.30 (d, 1H),







7.20-7.10 (d, 1H), 7.00-6.90 (d, 2H),







6.90-6.80 (d, 2H), 4.40-4.30 (t, 2H),







3.00-2.90 (t, 2H), 2.90 (s, 3H),







2.80-2.60 (m, 8H), 2.30 (s, 3H)


47
TFA
384.91
498.92
DMSO
7.60-7.50 (t, 1H), 7.50-7.40 (d, 1H),







7.30-7.20 (m, 2H), 7.10-7.00 (d, 1H),







6.90-6.80 (d, 2H), 4.80-4.70 (t, 1H), 4.30-4.20 (t, 2H),







3.80 (s, 3H), 3.70-3.50 (m, 4H),







3.30-3.10 (m, 4H), 2.90 (s, 3H).


48
TFA
364.49
478.50
DMSO
7.40-7.10 (m, 4H), 7.00-6.80 (m, 3H),







4.80-4.70 (t, 1H), 4.30-4.10 (m, 2H), 3.80 (s, 3H),







3.60-3.40 (m, 4H), 3.20-3.00 (m, 4H),







2.90 (s, 3H), 2.30 (s, 3H).


49
TFA
402.90
516.91
DMSO
7.60-7.50 (t, 1H), 7.50-7.30 (m, 2H),







7.10-7.05 (t, 1H), 6.90-6.70 (m, 2H), 5.10-4.90 (t,







1H), 4.30-4.20 (t, 2H), 3.80 (s, 3H),







3.70-3.60 (m, 4H), 3.30-3.10 (m, 4H), 2.90 (s,







3H).


50
TFA
382.48
496.49
DMSO
7.50-7.40 (m, 1H), 7.30-7.20 (m, 2H),







7.00-6.90 (d, 1H), 6.90-6.70 (m, 2H),







5.10-4.90 (t, 1H), 4.30-4.10 (t, 2H), 3.80 (s, 3H),







3.70-3.60 (m, 4H), 3.30-3.10 (m, 4H), 2.90 (s,







3H), 2.30 (s, 3H).


51
TFA
372.87
486.89
DMSO
7.60-7.50 (t, 1H), 7.50-7.30 (m, 3H),







7.20-7.00 (m, 3H), 4.90-4.70 (t, 1H), 4.30-4.20 (t,







2H), 3.70-3.50 (m, 4H), 3.30-3.10 (m, 4H),







2.80 (s, 3H).


52
TFA
352.46
466.47
DMSO
7.40-7.20 (m, 4H), 7.20-7.10 (m, 2H),







6.90-6.85 (m, 1H), 4.90-4.70 (t, 1H),







4.30-4.10 (m, 2H), 3.30-3.10 (m, 4H), 3.10-3.00 (m,







4H), 2.90 (s, 3H), 2.30 (s, 3H).


53
TFA
345.88
459.89
CD3OD
7.41 (s, 1H), 7.21 (d, 1H), 7.02 (d, 1H),







4.5 (s, 2H), 4.2-4.35 (m, 3H), 3.9-4.01 (m, 3H),







3.4-3.47 (m, 3H), 3.2-3.35 (m, 6H),







2.0-2.1 (m, 2H), 1.9-1.99 (m, 2H).


54
TFA
313.45
427.46
CD3OD
8.4 (bs, 1H), 7.21 (s, 1H), 7.19 (d, 1H),







6.9 (d, 1H), 4.22 (d, 1H), 3.96-4.18 (m, 3H),







3.82-3.92 (m, 2H), 3.5 (s, 3H), 3.22-3.4 (m,







5H), 2.4 (s, 3H), 1.1 (d, 6H).


55
HCL
340.47
376.92
CD3OD
7.21 (s, 1H), 7.19 (d, 1H), 6.9 (d, 1H),







5.27-5.42 (m, 1H), 4.5 (s, 2H), 4.09-4.2 (m, 3H),







3.9-4.0 (m, 2H), 3.5 (s, 3H), 2.4 (s, 3H),







1.9-2.1 (m, 2H), 1.7-1.85 (m, 6H).


56
OXALATE
338.88
428.91
CD3OD
7.50 (s, 1H), 7.40-7.30 (d, 1H),







7.35-7.20 (m, 3H), 7.20-7.10 (d, 1H), 7.00-7.80 (m,







2H), 4.40-4.30 (t, 2H), 3.40-3.30 (t, 2H),







3.30-3.20 (t, 2H), 3.20-3.00 (t, 2H), 2.80 (s,







3H), 2.80-2.70 (m, 4H).


57
TFA
359.90
473.92
CD3OD
7.42 (s, 1H), 7.22 (d, 1H), 7.09 (d, 1H),







4.6 (s, 2H), 4.2-4.3 (m, 3H), 3.9-4.0 (m, 3H),







3.6-3.8 (m, 6H), 3.5 (s, 3H), 3.4 (m, 3H),







1.45-1.9 (m, 6H). 10.7 (bs, 1H), 7.57 (s,







1H), 7.40 (d, 1H), 7.06 (d, 1H), 5.20 (d, 2H),







3.55-3.63 (m, 4H), 3.47-3.54 (m, 4H),







3.30-3.39 (m, 2H), 3.12-3.22 (m, 2H),







2.93-3.02 (m, 2H), 2.88 (s, 3H), 1.50-1.67 (m, 4H),







1.35-1.48 (m, 2H).


58
TFA
390.86
504.88
DMSO
7.62-7.50 (t, 1H), 7.50-7.30 (t, 3H),







7.25-7.00 (m, 2H), 4.85-4.75 (m, 1H),







4.30-4.20 (t, 2H), 3.80-3.60 (m, 4H), 3.25-3.10 (m,







4H), 2.90 (s, 3H).


59
TFA
370.45
484.46
DMSO
7.50-7.30 (m, 5H), 7.00-6.90 (t, 1H),







4.85-4.70 (t, 1H), 4.30-4.15 (m, 2H),







3.35-3.15 (m, 4H), 3.00-2.90 (m, 4H), 2.35 (s, 3H).


60
TFA
361.88
475.89
DMSO
11.2 (s, 1H), 7.5 (s, 1H), 7.3 (d, 1H),







7.05 (d, 1H), 4.2-4.4 (m, 3H), 3.7-3.9 (m, 4H),







3.5-3.65 (m, 4H), 3.42-3.49 (m, 6H),







3.3-3.4 (m, 6H), 3.12-3.2 (m, 3H).


61
OXALATE
356.87
446.90
CD3OD
7.60-7.50 (m, 3H), 7.30-7.20 (m, 3H),







7.20-7.10 (d, 1H), 4.00-3.80 (m, 6H),







3.80-3.70 (m, 4H), 3.60-3.50 (m, 5H)


62
OXALATE
318.47
408.49
CD3OD
7.40-7.30 (m, 5H), 7.20 (m, 1H),







7.20-7.10 (d, 1H), 7.0-6.80 (d, 1H), 4.0-3.80 (m, 4H),







3.80-3.70 (m, 2H), 3.40 (s, 3H),







3.30-3.20 (m, 6H), 2.40 (s, 3H).


63
TFA
336.46
450.47
CD3OD
7.40-7.20 (m, 3H), 7.20-7.00 (m, 3H),







6.90-6.80 (m, 1H), 4.40-4.20 (m, 6H),







3.20-3.00 (m, 6H), 3.00 (s, 3H), 2.40 (s, 3H).


67
TFA
402.90
516.92
DMSO
7.50 (s, 1H), 7.40-7.30 (t, 1H), 7.10-6.90 (m,







4H), 4.80-4.70 (t, 1H), 4.30-4.20 (t, 2H),







3.80 (s, 3H), 3.60-3.50 (m, 2H),







3.30-3.00 (m, 6H), 2.90 (s, 3H)


68
TFA
382.48
496.50
DMSO
7.30-7.20 (t, 1H), 7.20-6.80 (m, 5H),







4.80-4.70 (t, 1H), 4.30-4.10 (m, 2H), 3.70 (s, 3H),







3.20-3.00 (m, 8H), 2.90 (s, 3H), 2.30 (s,







3H).


69
TFA
352.91
466.93
CD3OD
7.60-7.50 (m, 2H), 7.40-7.30 (m, 2H),







7.30 (s, 1H), 7.20-7.10 (d, 1H), 7.0-6.90 (d, 1H),







4.0-3.80 (m, 4H), 3.70-3.50 (m, 2H),







3.40-3.20 (m, 9H), 2.40 (s, 3H).


72
DiHCL
360.89
433.80
DMSO
−11.3 (s, 1H), 9.5 (bs, 1H), 7.5 (s, 1H),







7.3 (d, 1H), 7.02 (d, 1H), 4.77 (s, 2H),







4.0-4.2 (m, 2H), 3.80-3.95 (m, 2H), 3.65-3.78 (m,







5H), 3.40 (s, 3H), 3.30-3.38 (m, 2H),







3.20-3.26 (m, 4H), 3.12-3.18 (m, 2H).


73
TFA
367.88
481.90
DMSO
−11.22 (s, 1H), 10.58 (s, 1H), 7.60 (d, 2H),







7.53 (s, 1H), 7.27-7.43 (m, 3H),







7.04-7.20 (m, 2H), 4.48-4.50 (m, 2H), 3.82-4.10 (m,







6H), 3.50 (s, 3H), 3.15-3.30 (m, 2H).


74
TFA
387.96
501.97
CD3OD
7.43 (s, 1H), 7.24 (d, 1H), 7.04 (d, 1H),







4.55 (s, 2H), 4.18-4.40 (m, 3H),







3.90-4.20 (m, 2H), 3.50 (s, 3H), 3.32-3.40 (m, 2H),







3.22-3.29 (m, 2H), 2.90 (s, 3H),







1.10-1.90 (m, 10H).


75
TFA
382.89
496.91
DMSO
−11.2 (s, 1H), 7.23-7.52 (m, 6H), 7.05 (d,







2H), 5.30 (s, 2H), 5.16-5.20 (m, 2H),







4.70-4.83 (m, 4H), 3.40 (s, 3H), 3.28-3.36 (m,







2H), 3.18-3.22 (m, 2H).


76
HCL
373.93
410.38
DMSO
−11.02 (bs, 1H), 7.57 (s, 1H), 7.38 (d, 1H),







7.04 (d, 1H), 5.05-5.27 (m, 2H),







4.20-4.27 (m, 1H), 3.93-4.04 (m, 1H), 3.52-3.63 (m,







2H), 3.0-3.26 (m, 4H), 2.90 (s, 3H),







2.50-2.63 (m, 4 H), 1.58-1.78 (m, 3H),







1.03-1.30 (m, 2H), 0.94 (d, 3H).


77
TFA
414.94
528.94
DMSO
7.60 (s, 1H), 7.50-7.40 (t, 1H),







7.10-7.00 (m, 2H), 6.95-6.85 (d, 2H), 5.60-5.50 (m,







2H), 4.80-4.70 (m, 2H), 4.30-4.10 (m, 4H),







3.70 (s, 3H), 3.60 (s, 3H), 3.30-3.10 (m,







2H), 2.95 (s, 3 H).


78
TFA
366.89
480.89
CD3OD
7.60-7.50 (m, 2H), 7.50-7.40 (m, 2H),







7.20-7.18 (d, 1H), 7.10-6.90 (d, 2H),







6.80-6.70 (d, 2H), 4.80-4.79 (d, 2H), 3.80 (s, 3H),







3.80-3.70 (m, 3H), 3.40-3.30 (m, 2H),







3.10 (s, 3H).


79
HCL
347.46
383.92405
CD3OD
10.3 (bs, 1H), 7.62 (d, 2H), 7.35 (t, 2H),







7.21 (s, 1H), 7.16-7.20 (m, 2H), 6.93 (d,







1H), 4.40-4.50 (m, 2H), 4.20-4.30 (m, 3H),







3.90-4.05 (m, 2H), 3.60 (s, 3H), 2.40 (s,







3H).


81
HCL
381.57
418.03
DMSO
10.62 (bs, 1H), 7.23-7.30 (m, 2H), 6.90 (t,







1H), 4.17-4.40 (m, 2H), 3.03-3.34 (m, 7H),







2.86-3.02 (m, 4H), 2.53-2.97 (m, 6H),







2.32 (s, 3H), 1.00-1.78 (m, 10H).









Example 126
Preparation of N-cyclohexyl-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-methylacetamide (Compound No. 232)
Sodium hydride (50%) (46 mg, 1.16 mmol) was dissolved in THF (2 mL) at 0° C. and stirred for 10 min. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol) in THF (3 mL) was added dropwise to the reaction mixture at 0° C. and stirred for 10 min. A solution of 2-chloro-N-cyclohexyl-N-methylacetamide (106 mg, 0.56 mmol) was added to the reaction mixture which was stirred at RT for 2 h. The reaction mixture was quenched with ice water, and a white solid was obtained. The solid was filtered, washed with diethyl ether and dried under vacuum to obtain 80 mg of product. The product was treated with ethanolic HCl to afford 74 mg of product as the HCl salt. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 7.20 (m, 2H), 6.84 (d, 1H), 5.20-5.04 (m, 2H), 4.10 (m, 1H), 3.80-3.70 (m, 4H), 3.20-3.00 (m, 8H), 2.90 (s, 2H), 2.42 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 4H), 1.40-1.25 (m, 2H), 1.26-1.20 (m, 2H).
Example 127
Preparation of (E)-6-(2-fluorostyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 233)
A solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol (100 mg, 0.28 mmol), triethylamine (0.59 mL, 0.42 mmol) in DCM (6 mL), was stirred for 10 min. at 0° C. Methane sulfonyl chloride (0.026 mL, 0.32 mmol) was added slowly at 0° C. and stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in NMP (0.7 mL), KOH powder (160 mg, 2.8 mmol) was added and heated at 90° C. for 14 h. The reaction was monitored by LCMS. Inorganic material was filtered off and the filtrate was purified by reverse phase chromatography to afford 20 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.60 (m, 2H), 7.50-7.40 (d, 1H), 7.40-7.20 (m, 2H), 7.20-7.00 (m, 3H), 6.90-6.80 (d, 1H), 3.80-3.70 (m, 4H), 3.50-3.40 (m, 4H), 3.15 (s, 3H), 2.40 (s, 3H).
Example 128
Preparation of (E)-9-chloro-6-(4-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 234)
A solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol (100 mg, 0.268 mmol) and triethylamine (0.055 mL, 0.402 mmol) in DCM (6 mL) was stirred at 0° C. for 10 min. Methane sulfonyl chloride (0.022 mL, 0.295 mmol) was added slowly at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in NMP (1 mL), KOH powder (105 mg, 1.87 mmol) was added at RT and heated at 90° C. for 14 h. the reaction mixture was monitored by LCMS. Inorganic material was filtered off and filtrate was purified by reverse phase chromatography to afford 15 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H), 7.20-7.10 (m, 3H), 6.80-6.70 (d, 2H), 3.80-3.70 (m, 2H), 3.50-3.40 (m, 2H), 3.30-3.10 (d, 4H), 3.15 (s, 3H).
Example 129
Preparation of (E)-6-(4-chlorostyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 235)
1-(4-Chlorophenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol (100 mg, 0.271 mmol) was dissolved in DCM (5 mL) and triethylamine (0.056 mL, 0.406 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min. Methane sulfonyl chloride (0.023 mL, 0.298 mmol) was added slowly at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in NMP (0.8 mL), KOH powder (106 mg, 1.88 mmol) was added at RT and the mixture then heated at 90° C. for 14 h. The product was detected by LCMS. Inorganic material was filtered off and the filtrate was purified by reverse phase chromatography to afford 10 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.60 (d, 4H), 7.50-7.40 (t, 3H), 7.30-7.20 (m, 1H), 6.90-6.80 (d, 1H), 3.80-3.70 (m, 2H), 3.50-3.40 (m, 2H), 3.30-3.20 (d, 4H), 3.15 (s, 3H), 2.40 (s, 3H).
Example 130
Preparation of (E)-9-chloro-6-(3,4-difluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 236)
2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanol (150 mg, 0.384 mmol) was dissolved in DCM (10 mL), triethylamine (0.079 mL, 0.576 mmol) was added and the mixture stirred for 10 min. Methane sulfonyl chloride (0.032 mL, 0.432 mmol) was added slowly at 0° C. and stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude mixture was dissolved in NMP (1.5 mL), KOH powder (150 mg, 2.68 mmol) was added at RT and the reaction mixture was heated at 90° C. for 14 h. The product was detected by LCMS. Inorganic material was filtered off and the filtrate was purified by reverse phase chromatography to afford 5 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H), 7.30-7.10 (m, 3H), 6.90-6.70 (d, 1H), 3.80-3.70 (m, 4H), 3.60-3.40 (m, 4H), 3.15 (s, 3H).
Example 131
Preparation of 6-(2-fluorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 237)
2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethyl methanesulfonate (530 mg, 0.001177 mol) was dissolved in methanol and 10% Pd—C (62 mg, 0.5885 mmol) was added. A drop of water was added and the reaction mass is stirred at RT for 24 h under hydrogen atmosphere. The reaction mass was filtered through Celite and the filtrate concentrated to obtain the crude compound. The crude was purified by preparative HPLC to obtain 140 mg desired compound. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.60 (s, 1H), 7.30-7.20 (m, 2H), 7.20-7.15 (d, 1H), 7.10-7.00 (t, 12H), 7.00-6.90 (t, 1H), 6.90-6.80 (t, 1H), 4.40-4.30 (t, 2H), 3.90-3.85 (t, 2H), 3.60-3.50 (t, 2H), 3.30-3.10 (m, 4H), 3.10 (t, 2H), 2.90 (s, 3H).
Example 132
Preparation of (E)-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 238)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.35 (s, 1H), 7.18 (m, 2H), 7.05 (d, 1H), 6.98 (d, 1H), 6.70 (m, 2H), 3.60 (m, 2H), 3.10 (m, 5H), 2.90 (s, 3H), 2.60 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H).
Example 133
Preparation of (E)-9-chloro-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 239)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (d, 2H), 7.32 (m, 2H), 7.20 (s, 2H), 6.50 (s, 1H), 3.95 (m, 2H), 3.60-3.20 (m, 6H), 3.05 (s, 3H), 1.80 (s, 3H).
Example 134
Preparation of (Z)-6-(2-(2-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 240)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.15 (m, 3H), 7.05 (d, 1H), 6.95 (t, 1H), 6.85 (t, 1H), 6.75 (s, 1H), 6.70 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.10 (m, 2H), 2.85 (m, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.33 (m, 2H), 2.30 (s, 3H).
Example 135
Preparation of (E)-6-(2-(2-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 241)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.42 (m, 1H), 7.33 (m, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 7.18 (dd, 1H), 7.11 (d, 1H), 7.09 (d, 1H), 6.72 (s, 1H), 3.82 (m, 2H), 3.40 (m, 1H), 3.30 (m, 5H), 3.0 (s, 3H), 2.45 (s, 3H), 1.90 (s, 3H).
Example 136
Preparation of (Z)-9-chloro-6-(2-(2-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 242)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.36 (d, 1H), 7.18 (m, 1H), 7.11 (s, 1H), 6.98 (dd, 1H), 6.92 (m, 3H), 6.86 (s, 1H), 3.60 (m, 2H), 3.10 (m, 3H), 3.0 (s, 3H), 2.90 (m, 3H), 2.30 (s, 3H).
Example 137
Preparation of (E)-9-chloro-6-(2-(2-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 243)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.56 (dd, 1H), 7.53 (s, 1H), 7.40 (m, 1H), 7.30 (d, 1H), 7.20 (m, 3H), 6.80 (s, 1H), 3.80 (m, 2H), 3.40 (m, 3H), 3.30 (m, 2H), 3.15 (m, 1H), 3.05 (s, 3H), 1.85 (s, 3H).
Example 138
Preparation of (Z)-9-chloro-6-(2-(2-chlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 244)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.34 (m, 2H), 7.24 (d, 1H), 7.12 (d, 2H), 6.95 (m, 1H), 6.70 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.25 (m, 2H), 3.10 (m, 2H), 3.0 (m, 2H), 2.80 (s, 3H), 2.34 (s, 3H)
Example 139
Preparation of (E)-9-chloro-6-(2-(2-chlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 245)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (m, 2H), 7.35 (m, 2H), 7.20 (m, 3H), 6.50 (s, 1H), 3.90 (m, 2H), 3.50 (m, 1H), 3.35 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.0 (m, 5H).
Example 140
Preparation of (E)-9-chloro-3-methyl-6-(2-(pyridin-3-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 246)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.85 mmol) was dissolved in DMF (6 mL), CuI (16 mg, 0.085 mmol), L-proline (19 mg, 0.17 mmol), K3PO4 (364 mg, 1.70 mmol) were added and stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (203 mg, 1.02 mmol) was added dropwise and the reaction mixture was heated at 90° C. for 18 h. DMF was evaporated under reduced pressure and the reaction mixture was poured into water (10 mL). The aqueous mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography to 140 mg of the desired compound. 1NMR (CD3OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.62 (d, 1H), 7.90 (m, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.20 (m, 2H), 3.80 (m, 2H), 3.42 (m, 4H), 3.22 (m, 2H), 3.10 (s, 3H), 2.0 (s, 3H).
Example 141
Preparation of (E)-3,9-dimethyl-6-(2-(pyridin-3-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 247)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.934 mmol) was dissolved in DMF (6 mL), CuI (17.7 mg, 0.09 mmol), L-proline (21 mg, 0.18 mmol), K3PO4 (397 mg, 1.86 mmol) was added and stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (222 mg, 1.12 mmol) was added dropwise and the reaction mixture was heated at 90° C. for 18 h. DMF was evaporated under reduced pressure, 10 mL water was added and the mixture extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to 180 mg of the desired compound. 1HNMR (CD3OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.70 (d, 1H), 8.0 (t, 1H), 7.36 (s, 2H), 7.08 (m, 2H), 3.80 (m, 2H), 3.40 (m, 4H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 1.05 (s, 3H).
Example 142
Preparation of (E)-9-chloro-3-methyl-6-(2-(pyridin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 248)
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (117 mg, 0.5 mmol) and potassium phosphate tribasic (212 mg, 1 mmol) in DMF was purged with nitrogen and heated at 90° C. 4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol) in DMF were charged in a separate flask. This mixture was purged with nitrogen and heated at 90° C. for 5 min. Both reaction mixtures were combined and heated at 90° C. overnight. The reaction mixture was poured into water to obtain a precipitate. The precipitate was filtered and purified with silica column chromatography (100-200 mesh) by neutralizing the silica gel with 2-3 drops of aq. NH3 and using 0-2% MeOH:DCM as eluant. Compound was further purified by reverse phase HPLC to obtain the product. 1HNMR (CD3OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 7.70 (d, 1H), 7.58 (d, 1H), 7.20 (s, 2H), 3.70 (m, 2H), 3.40 (m, 2H), 3.30 (m, 4H), 3.05 (s, 3H), 2.02 (s, 3H).
Example 143
Preparation of (Z)-9-chloro-6-(2-(3-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 249)
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.45 (s, 1H), 7.25 (d, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 6.92 (t, 1H), 6.82 (s, 1H), 6.62 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.30-3.0 (m, 4H), 2.90 (s, 3H), 2.70 (m, 2H), 2.35 (s, 3H).
Example 144
Preparation of (E)-9-chloro-6-(2-(3-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 250)
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.58 (s, 1H), 7.42 (m, 3H), 7.15 (m, 3H), 7.05 (s, 1H), 3.80 (m, 2H), 3.40 (m, 2H), 3.30 (m, 4H), 3.05 (s, 3H), 1.90 (s, 3H).
Example 145
Preparation of (Z)-6-(2-(3-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 251)
A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.30 (s, 1H), 7.16 (m, 2H), 7.0 (d, 1H), 6.92 (t, 1H), 6.85 (s, 1H), 6.70 (d, 1H), 6.62 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.25 (m, 1H), 3.10 (m, 1H), 2.95 (m, 2H), 2.90 (s, 3H), 2.70 (m, 2H), 2.42 (s, 3H), 2.30 (s, 3H).
Example 146
Preparation of (E)-6-(2-(3-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 252)
A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.45 (m, 2H), 7.40 (d, 1H), 7.36 (s, 1H), 7.10 (m, 1H), 7.0 (m, 3H), 3.80 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H), 3.05 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Example 147
Preparation of (E)-3,9-dimethyl-6-(2-(pyridin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 253)
3,9-Dimethyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (107.5 mg, 0.5 mmol), potassium phosphate tribasic (212 mg, 1 mmol) in DMF and the mixture purged with nitrogen. The reaction mass was heated at 85° C. for 5 min. In another flask was added 4-(1-bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol) in DMF. This mixture was purged with nitrogen and heated at 90° C. for 5 min. The reaction mixtures were combined and heated at 90° C. overnight. The reaction mass was poured into water to obtain a precipitate. The precipitate was filtered and purified with silica column chromatography (100-200 mesh), by neutralizing the silica gel with 2-3 drops of aq. ammonia and using 0-2% MeOH:DCM as eluant. The compound was further purified by reverse phase HPLC to obtain the product. 1HNMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 8.10 (d, 2H), 7.62 (s, 1H), 7.38 (s, 1H), 7.05 (d, 2H), 3.80 (m, 2H), 3.40 (m, 2H), 3.30 (m, 2H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).
Example 148
Preparation of 6-(4-fluorostyryl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 39)
To a solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol (150 mg, 0.42 mmol) in DCM (7 mL), triethylamine (0.088 mL, 0.63 mmol) was added and stirred for 10 min, methane sulfonyl chloride (0.036 mL, 0.47 mmol) were added slowly at 0° C. and stirred at RT for 2 h. Reaction was monitored by TLC. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was dissolved in NMP (0.8 mL), KOH powder (166 mg, 2.97 mmol) was added at RT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixture was diluted with methanol, inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 10 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H), 7.30 (s, 1H), 7.20-7.00 (m, 3H), 6.80-6.70 (d, 1H), 3.90-3.75 (m, 4H), 3.50-3.40 (m, 4H), 3.15 (s, 3H), 2.35 (s, 3H).
Example 149
Preparation of (Z)-9-chloro-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 152)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and K3PO4 (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% methanol-dichloromethane. The product was further purified by reverse phase HPLC. Yield: 8 mg. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.38 (s, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.70 (m, 2H), 3.70 (m, 2H), 3.10 (m, 4H), 2.90 (s, 3H), 2.60 (m, 2H), 2.30 (s, 3H).
Example 150
Preparation of (E)-9-chloro-6-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 154)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (74 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol) and K3PO4 (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 74 mg. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.62 (d, 2H), 7.57 (s, 1H), 7.18 (d, 2H), 7.10 (d, 1H), 3.78 (m, 2H), 3.40 (m, 4H), 3.20 (m, 2H), 3.06 (s, 3H), 1.90 (s, 3H).
Example 151
Preparation of (E)-9-chloro-6-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 155)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (84 mg, 0.359 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol) and K3PO4 (183 mg, 0.862 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 55 mg. 1HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.82 (m, 1H), 7.62 (s, 1H), 7.55 (m, 2H), 7.20 (m, 2H), 7.12 (d, 1H), 3.38 (m, 4H), 3.10 (m, 4H), 2.90 (s, 3H), 1.80 (s, 3H).
Example 152
Preparation of (E)-9-chloro-6-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 157)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (80 mg, 0.34 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol) and K3PO4 (145 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 46 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.58 (s, 1H), 7.42 (m, 2H), 7.16 (m, 3H), 6.95 (s, 1H), 3.90 (s, 3H), 3.60 (m, 4H), 3.25 (m, 4H), 3.05 (s, 3H), 1.82 (s, 3H).
Example 153
Preparation of (E)-6-(3-fluoro-4-methoxystyryl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (Compound No. 158)
To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (110 mg, 0.273 mmol) in DCM (5 mL), triethylamine (0.056 mL, 0.406 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.024 mL, 0.03 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in NMP (0.8 mL), KOH powder (105 mg, 1.8 mmol) was added at RT and heated at 90° C. for 14 h. Product was detected by LCMS. Inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 18 mg of TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m, 4H), 7.40-7.30 (d, 1H), 7.25-7.15 (t, 2H), 6.80-6.70 (d, 1H), 3.95 (s, 3H), 3.70-3.60 (m, 4H), 3.00-2.90 (m, 4H), 2.45 (s, 3H).
Example 154
Preparation of (E)-9-chloro-1,2,3,4,5,6-hexahydro-6-(2-(4-methoxyphenyl)prop-1-enyl)-3-methylazepino[4,5-b]indole (Compound No. 160)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (43 mg, 0.184 mmol) was dissolved in DMF (4 mL) Copper (I) iodide (4 mg, 0.0184 mmol) L-proline (4.2 mg, 0.037 mmol) and K3PO4 (78 mg, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (50 mg, 0.22 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, Oxalate salt) δ (ppm): 7.60 (m, 3H), 7.10 (m, 2H), 6.98 (m, 3H), 3.80 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H), 2.82 (s, 3H), 1.80 (s, 3H).
Example 155
Preparation of (Z)-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 174)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and K3PO4 (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% methanol-dichloromethane. The product was further purified by reverse phase HPLC. Yield: 30 mg. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (s, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 7.18 (d, 1H), 7.05 (d, 1H), 6.56 (s, 1H), 3.90 (m, 2H), 3.40 (m, 1H), 3.22 (m, 5H), 3.0 (s, 3H), 2.42 (s, 3H), 1.82 (s, 3H)
Example 156
Preparation of (E)-6-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 176)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (67 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol) and K3PO4 (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 53 mg. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.82 (s, 1H), 7.60 (s, 2H), 7.36 (d, 1H), 7.10 (d, 1H), 7.0 (m, 2H), 3.78 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H), 3.08 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Example 157
Preparation of (E)-6-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 177)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (77 mg, 0.36 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (8 mg, 0.036 mmol), L-proline (9 mg, 0.086 mmol) and K3PO4 (183 mg, 0.86 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 52 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.60 (m, 1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.0 (s, 3H), 3.60 (m, 4H), 3.25 (m, 4H), 3.05 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Example 158
Preparation of (E)-6-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 179)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (73 mg, 0.34 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol) and K3PO4 (145 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 70 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.42 (s, 1H), 7.40 (d, 1H), 7.30 (s, 1H), 7.15 (t, 1H), 7.02 (m, 2H), 6.96 (s, 1H), 3.90 (s, 3H), 3.60 (m, 4H), 3.22 (m, 4H), 3.05 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Example 159
Preparation of (E)-6-(3-fluoro-4-methoxystyryl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (Compound No. 180)
To a solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (160 mg, 0.04 mmol) in DCM (7 mL), triethylamine (0.087 mL, 0.082 mmol) were added and stirred for 10 min., methane sulfonyl chloride (0.022 mL, 0.035 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in NMP (0.8 mL), KOH powder (164 mg, 2.93 mmol) was added at RT and heated at 90° C. for 14 h. Product was detected by LCMS. Inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 38 mg of TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m, 3H), 7.50-7.30 (m, 2H), 7.30-7.20 (t, 1H), 7.10-7.00 (d, 1H), 6.80-6.70 (d, 1H), 3.95 (s, 3H), 3.85-3.80 (m, 4H), 3.00-2.80 (m, 2H), 2.95 (s, 3H), 2.45 (s, 2H), 2.38 (s, 3H).
Example 160
Preparation of (E)-1,2,3,4,5,6-hexahydro-6-(2-(4-methoxyphenyl)prop-1-enyl)-3,9-dimethylazepino[4,5-b]indole (Compound No. 182)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (78 mg, 0.36 mmol) was dissolved in DMF (5 mL) Copper (I) iodide (7 mg, 0.036 mmol) L-proline (8 mg, 0.073 mmol) and K3PO4 (156 mg, 0.734 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.62 (d, 2H), 7.30 (s, 1H), 7.0 (m, 4H), 6.95 (d, 1H), 3.80 (s, 3H), 3.40 (m, 4H), 3.10 (m, 4H), 2.80 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Example 161
Preparation of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone (Compound No. 224)
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. tert-Butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (147 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl (38 mg). The NMR confirmed removal of the Boc group when ethanolic HCl was used. 1H NMR (CD3OD, DiHCl salt) δ (ppm): 7.3 (s, 1H), 7.22 (d, 1H), 7.0 (d, 1H), 5.23 (d, 2H), 3.95-4.10 (m, 4H), 3.7-3.9 (m, 4H), 3.36-3.43 (m, 4H), 3.1-3.22 (m, 4H), 3.0 (s, 3H), 2.4 (s, 3H).
Example 162
Preparation of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone (Compound No. 225)
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. 2-Chloro-1-(4-methylpiperidin-1-yl)ethanone (98 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 11.22 (bs, 1H), 7.20 (m, 2H), 5.0-5.20 (m, 2H), 4.23 (d, 1H), 4.0 (d, 1H), 3.5-3.6 (m, 2H), 3.0-3.23 (m, 4H), 2.8-2.95 (m, 2H), 2.26-2.42 (m, 2H), 1.5-1.8 (m, 3H), 1.09-1.2 (m, 1H), 0.96 (d, 3H).
Example 163
Preparation of (E)-9-chloro-6-(3,4-dimethoxystyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 226)
To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol (300 mg, 0.722 mmol) in DCM (5 mL), triethylamine (0.15 mL, 1.077 mmol) were added and stirred for 10 min., methane sulfonyl chloride (0.062 mL, 0.795 mmol) was added slowly at 0° C. and stirred at the same temperature for 1 h, then at RT for 2 h. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography. The pure product was dissolved in NMP (2.0 mL), KOH powder (283 mg, 5.06 mmol) was added at RT and heated at 90° C. for 14 h. Product was detected by LCMS. The reaction mixture was diluted with methanol, filtered and evaporated. Crude product was purified by reverse phase chromatography to get 18 mg of pure product as TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m, 2H), 7.35 (s, 1H), 7.30-7.20 (d, 1H), 7.20-7.15 (d, 1H), 7.00-6.90 (d, 1H), 6.80-6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.80-3.60 (m, 2H), 2.95 (s, 3H), 2.90-2.80 (m, 2H), 2.60-2.30 (m, 4H).
Example 164
Preparation of 1-(3,4-dimethoxyphenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol (Compound No. 227)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33 mmol) was dissolved in DMF (6 ml). A solution of sodium hydride (50%) (168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3,4-dimethoxyphenyl)oxirane (630 mg, 3.50 mmol) in DMF (4 ml) was added dropwise for 10 min and stirred for 14 h at RT. Reaction was monitored by LCMS. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to get 50 mg of pure product. 1H NMR (CDCl3, Oxalate salt) δ (ppm): 7.40-7.30 (m, 2H), 7.10-7.00 (m, 1H), 6.90-6.80 (t, 2H), 6.80-6.60 (t, 1H), 5.00-4.80 (t, 2H), 4.30-4.20 (m, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.00-2.90 (m, 4H), 2.80 (s, 3H), 2.75-2.70 (m, 2H), 2.35 (s, 3H).
Example 165
Preparation of (E)-9-chloro-3-methyl-6-styryl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 228)
To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol (100 mg, 0.28 mmol) in DCM (6 mL), triethylamine (0.06 mL, 0.42 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.024 mL, 0.31 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction was monitored by TLC. Reaction mixture was diluted with DCM washed with water. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was dissolved in NMP (0.7 mL), KOH powder (158 mg, 2.82 mmol) was added at RT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixture was diluted with methanol, inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 8 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.60 (m, 5H), 7.50-7.40 (t, 2H), 7.30-7.20 (d, 1H), 7.22-7.10 (d, 1H), 6.90-6.80 (d, 1H), 3.85-3.75 (m, 4H), 3.45-3.40 (m, 4H), 3.15 (s, 3H).
Example 166
Preparation of (E)-3,9-dimethyl-6-styryl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 229)
To a solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol (100 mg, 0.299 mmol) in DCM (2 mL), triethylamine (0.062 mL, 0.44 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.025 mL, 0.32 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction was monitored by TLC. The reaction mixture was diluted with DCM washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was dissolved in NMP (0.7 mL), KOH powder (117 mg, 2.09 mmol) was added at RT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixture was diluted with methanol, inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 20 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.50 (m, 5H), 7.40-7.20 (m, 3H), 7.15-7.00 (d, 1H), 6.80-6.70 (d, 1H), 3.90-3.80 (t, 2H), 3.60-3.50 (m, 4H), 3.35-3.20 (t, 2H), 3.15 (s, 3H), 2.40 (s, 3H).
Example 167
Preparation of (E)-6-(2-fluoro-4-methoxystyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 230)
To a solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol (200 mg, 0.52 mmol) in DCM (10 mL), triethylamine (0.11 mL, 0.78 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.044 mL, 0.56 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction was monitored by TLC. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in NMP (0.8 mL), KOH powder (205 mg, 3.66 mmol) was added at RT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixture was diluted with methanol, inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 25 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.60 (m, 2H), 7.60-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.30-7.25 (m, 1H), 7.18-7.10 (d, 1H), 6.90-6.80 (m, 2H), 3.80 (s, 3H), 3.60-3.50 (m, 4H), 3.40-3.30 (m, 4H), 3.15 (s, 3H), 2.41 (s, 3H).
Example 168
Preparation of (E)-3,9-dimethyl-6-(2-(pyrimidin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 254)
4-(1-bromoprop-1-en-2-yl)pyrimidine (236 mg, 1.2 mmol) was dissolved in DMF (5 mL) and was added K3PO4 (424 mg, 2 mmol) followed by the addition of Copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole (214 mg, 1 mmol) was added and purged nitrogen for 2 min. Reaction mass was stirred at 85 degree C. for overnight. Water was added and filtered the solid mass under vacuum. Crude was purified on silica gel (100-200 mesh) using 0-10% methanol: dichloromethane as eluent. Yield: 72 mg. 1H NMR (CDCl3, Oxalate salt) δ (ppm): 9.20 (s, 1H), 8.76 (s, 1H), 8.0 (s, 1H), 7.44 (d, 1H), 7.30 (s, 1H), 7.0 (s, 2H), 2.99 (m, 4H), 2.84 (m, 4H), 2.50 (s, 3H), 2.42 (s, 3H), 2.04 (s, 3H).
Example 169
Preparation of 9-chloro-6-((4-fluorophenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 281)
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol) was dissolved in toluene (4 mL) and the reaction mixture stirred for 10 min. K2CO3 (276 mg, 0.2 mmol), CuSO4.5H2O (249 mg, 0.01 mmol) and 1,10-Phenanthroline (36 mg, 0.2 mmol) were added to the reaction mixture and again stirred for 10 min. 1-(Bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) in toluene (2 mL) was added and reaction mixture was heated at 80-85° C. overnight. Toluene was evaporated under reduced pressure to obtain the crude compound. The crude was purified by silica gel (100-200 mesh) column chromatography using 0-100% Hexane:Ethyl acetate as eluent followed by reverse phase chromatography to obtain the product as TFA salt. 1H NMR CD3OD, TFA salt) δ (ppm): 7.60 (m, 2H), 7.30 (m, 2H), 7.18 (m, 2H), 7.08 (m, 1H), 3.60 (m, 4H), 3.46 (m, 2H), 3.20 (m, 2H), 3.05 (s, 3H)
Example 170
Preparation of 9-chloro-6-((4-chlorophenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 282)
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (235 mg, 1 mmol), CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-Phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (10 mL) was flushed with nitrogen heated 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (silica gel, 60-80% ethyl acetate in hexane) to get 37 mg of product. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.50 (s, 1H) 7.49-7.40 (m, 3H), 7.38-7.32 (m, 2H), 7.25-7.20 (d, 1H), 3.22-3.18 (m, 2H), 3.0-2.90 (m, 6H), 2.60 (s, 3H).
Example 171
Preparation of 9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 283)
9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol), CuSO4.5H2O (21 mg, 0.085 mmol), 1,10-Phenanthroline (30 mg, 0.17 mmol) and K3PO4 (180 mg, 0.85 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (131 mg, 0.46 mmol) in toluene (5 mL) were charged and flushed with nitrogen. The reaction mixture was heated at 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get 9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole which was further purified by prep TLC to get 24 mg of product. 1HNMR (CDCl3, freebase) δ (ppm): 7.40 (d, 2H), 7.30 (m, 2H), 7.20 (d, 1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H).
Example 172
Preparation of 6-((3-fluoro-4-methoxyphenyl)ethynyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 284)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), CuSO4.5H2O (23 mg, 0.093 mmol), 1,10-Phenanthroline (33 mg, 0.18 mmol) and K3PO4 (197 mg, 0.93 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (116 mg, 0.51 mmol) in toluene (5 mL) were added and flushed with nitrogen. The reaction mixture was heated at 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get 6-((3-fluoro-4-methoxyphenyl)ethynyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole which was repurified by prep TLC to get 8 mg product as brown solid. 1HNMR (CDCl3, freebase) δ (ppm): 7.40 (d, 1H), 7.22 (m, 3H), 7.10 (d, 1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.15 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H), 2.42 (s, 3H).
Example 173
Preparation of 1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)ethanone (Compound No. 285)
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 10 mmol) was dissolved in toluene (3 mL) and stirred for 10 min. K2CO3 (276 mg, 0.2 mmol), CuSO4.5H2O (249 mg, 0.01 mmol) and 1,10-Phenanthraline (36 mg, 0.2 mmol) were added to the reaction mixture and stirred at RT for 10 min. 1-(Bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) in toluene (2 mL) was added and the reaction mixture was heated to 80-85° C. overnight. The toluene was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography using 0-5% MeOH in dichloromethane as eluent followed by reverse phase chromatography to obtain the product as TFA salt. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.65 (m, 2H), 7.55 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 7.05 (m, 1H), 3.60 (m, 5H), 3.45 (m, 3H), 3.20 (m, 3H), 3.0 (s, 3H).
Example 174
Preparation of (E)-9-chloro-6-(2-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 83)
To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol (100 mg, 0.26 mmol) in DCM (2.5 mL), triethylamine (0.055 mL, 0.04 mmol) was added and stirred for 10 min, methanesulfonyl chloride (0.022 mL, 0.029 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reaction mixture was diluted with water, extracted with dichloromethane. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was taken in NMP (0.7 mL), KOH powder (105 mg, 1.8 mmol) was added at RT and heated at 90° C. for 14 h. The compound was purified by reverse phase chromatography to afford 9 mg of TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.80-7.70 (m, 2H), 7.60-7.50 (m, 2H), 7.35-7.25 (m, 1H), 7.20-7.10 (m, 3H), 6.90-6.80 (d, 1H), 3.90-3.80 (m, 4H), 3.60-3.50 (m, 4H), 3.15 (s, 3H).
Example 175
Preparation of (E)-9-chloro-6-(2-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 286)
4-(1-bromoprop-1-en-2-yl)pyrimidine (197 mg, 1 mmol) was dissolved in DMF (5 mL). To this solution was added K3PO4 (424 mg, 2 mmol) followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 9-Chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (234 mg, 1 mmol) was then added and the reaction mixture was purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the product was extracted with ethyl acetate. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) using 0-10% MeOH: DCM as eluent. The compound was further purified through reverse phase chromatography. Yield: 33 mg. 1H NMR (CD3OD, Oxalate salt) δ (ppm): 9.18 (s, 1H), 8.81 (d, 1H), 8.0 (s, 1H), 7.80 (d, 1H), 7.60 (s, 1H), 7.18 (m, 2H), 3.60 (m, 4H), 3.30 (m, 4H), 3.10 (s, 3H), 2.0 (s, 3H).
Example B1
Determination of the Ability of Compounds of the Invention to Bind a Histamine Receptor
Histamine H1
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine H1 receptor expressed in Chinese hamster ovary (CHO) cells (De Backer, M. D. et al., Biochem. Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 2 mM MgCl2, 100 mM NaCl, 250 mM Sucrose) was used. Compounds of the invention were incubated with 1.2 nM [3H]Pyrilamine for 180 min. at 25° C. Non-specific binding was estimated in the presence of 1 μM pyrilamine. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Pyrilamine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 6.
Histamine H2
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine H2 receptor expressed in Chinese hamster ovary (CHO) K1 cells (Ruat, M., Proc. Natl. Acad. Sci. USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used. Compounds of the invention were incubated with 0.1 nM [125I]Aminopotentidine for 120 min. at 25° C. Non-specific binding was estimated in the presence of 3 μM Tiotidine. Receptor proteins were filtered and washed, the filters were then counted to determine [125I]Aminopotentidine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 6.
Histamine H3
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine H3 receptor expressed in Chinese hamster ovary (CHO-K1) cells (Yanai K et al. Jpn J. Pharmacol. 65(2): 107, 1994; Zhu Y et al. Mol. Pharmacol. 59(3): 434, 2001) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 0.04% BSA) is used. Compounds of invention are incubated with 3 nM [3H]R(−)-α-Methylhistamine for 90 min. at 25° C. Non-specific binding is estimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptor proteins are filtered and washed, the filters are counted to determine [3H]R(−)-α-Methylhistamine specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Example B2
Determination of the Ability of Compounds of the Invention to Bind a Imidazoline I2 Receptor
Central Imidazoline I2 
To evaluate in radioligand binding assays the activity of compounds of the invention, rat central imidazoline I2 receptor obtained from Wistar Rat cerebral cortex (Brown, C. M. et al., Br. J. Pharmacol. 99:803, 1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) is used. Compounds of the invention are incubated with 2 nM [3H]Idazoxan for 30 min. at 25° C. Non-specific binding is estimated in the presence of 1 μM Idazoxan. Receptor proteins are filtered and washed, the filters are counted to determine [3H]Idazoxan specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.







TABLE 4







Binding data










Histamine Binding



Compound
(1 μM)









No.
H1
H2












1
96
58


2
93
105


3
102
82


4
100
59


5
100
62


6
103
52


7
101
52


8
97
68


9
99
44


10
101
78


11
97
7


12
99
98


13
98
92


14
98
83


15
100
92


16
103
92


17
101
84


18
98
51


19
99
42


20
99
37


21
96
13


22
12
5


23
58
−3


24
100
58


25
91
47


26
97
84


27
101
78


28
103
97


29
98
105


30
102
97


31
14
−10


32
11
−5


33
87
101


34
95
103


35
100
104


36
88
104


37
13
4


38
83
26


39
98
91


40
101
61


41
100
52


42
103
45


43
100
30


44
16
1


45
13
7


46
108
89


47
100
70


48
98
56


49
94
65


50
98
65


51
102
70


52
96
61


53
14
3


54
18
−3


55
15
−3


56
105
74


57
8
1


58
98
91


59
60
37


60
2
6


61
97
89


62
98
79


63
99
83


67
100
72


68
102
69


69
2
−9


72
−12
0


73
18
−5


74
25
9


75
20
−4


76
95
19


77
97
37


78
100
91


79
6
0


82
103
95


83
97
98


152
91
86


154
94
97


155
93
92


157
68
93


158
98
89


160
87
91


174
98
99


176
82
95


177
93
92


179
45
88


180
97
77


182
62
92


224
33
−4


225
95
6


226
99
39


227
95
19


228
99
97


229
100
94


230
95
89


232
95
22


233
98
94


234
99
92


235
97
94


236
99
97


237
96
81


238
98
98


239
91
89


240
96
87


241
98
93


242
100
98


243
93
84


244
102
99


245
96
88


246
96
48


247
82
36


248
88
44


249
98
97


250
93
85


251
96
95


252
93
87


253
32
31


281
56
76


282
99
87


283
12
83


284
11
4


285
68
74









Example B3
Determination of the Ability of Compounds of the Invention to Bind an Adrenergic Receptor
Adrenergic α1A 
To evaluate in radioligand binding assays the activity of compounds of the invention, rat adrenergic α1A receptor obtained from Wistar Rat submaxillary glands (Michel, A. D. et al., Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) is used. Compounds of the invention are incubated with 0.25 nM [3H]Prozosin for 60 min. at 25° C. Non-specific binding is estimated in the presence of 10 μM phentolamine. Receptor proteins are filtered and washed, the filters are counted to determine [3H]Prozosin specifically bound. Compounds of the invention are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Adrenergic α1B 
To evaluate in radioligand binding assays the activity of compounds of the invention, rat adrenergic α1B receptor obtained from Wistar Rat liver (Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun. 186:760, 1992; Michel A. D. et al., Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) is used. Compounds of the invention are incubated with 0.25 nM [3H]Prozosin for 60 min. at 25° C. Non-specific binding is estimated in the presence of 10 μM phentolamine. Receptor proteins are filtered and washed, the filters are counted to determine [3H]Prozosin specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Adrenergic α1D 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α1D receptor expressed in human embryonic kidney (HEK-293) cells (Kenny, B. A. et al. Br. J. Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds of invention were incubated with 0.6 nM [3H]Prozosin for 60 min. at 25° C. Non-specific binding was estimated in the presence of 10 μM phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Prozosin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 5.
Adrenergic α2A 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α2A receptor expressed in insect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 2 mM EDTA) was used. Compounds of invention were incubated with 1 nM [3H]MK-912 for 60 min. at 25° C. MK912 is (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2 h-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-one hydrochloride Non-specific binding was estimated in the presence of 10 μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride). Receptor proteins were filtered and washed, the filters were then counted to determine [3H]MK-912 specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 5.
Adrenergic α2B 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α2B receptor expressed in Chinese hamster ovary (CHO-K1) cells (Uhlen S et al. Eur J. Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA) was used. Compounds of the invention were incubated with 2.5 nM [3H]Rauwolscine for 60 min. at 25° C. Non-specific binding was estimated in the presence of 10 μM Prozosin. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Rauwolscine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 5.
Adrenergic α2C 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α2C receptor expressed in insect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 2 mM EDTA) is used. Compounds of the invention are incubated with 1 nM [3H]MK-912 for 60 min. at 25° C. Non-specific binding is estimated in the presence of 10 μM WB-4101. Receptor proteins are filtered and washed, the filters are counted to determine [3H]MK-912 specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Example B4
Determination of the Ability of Compounds of the Invention to Bind a Dopamine Receptor
Dopamine D2L 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant dopamine D2L receptor expressed in Chinese hamster ovary (CHO) cells (Grandy, D. K. et al. Proc. Natl. Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al., Mol. Endocrinol. 6:920, 1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mM Ascorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of the invention were incubated with 0.16 nM [3H]Spiperone for 120 min. at 25° C. Non-specific binding was estimated in the presence of 10 μM Haloperidol. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Spiperone specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 5.







TABLE 5







Inhibition of ligand binding to aminergic G protein-coupled receptors


by compounds of the invention:











Dopamine



Adrenergic (1 μM)
(1 μM)











Comp. No.
α1D
α2A
α2B
D2L














1
90
90
107
23


2
100
96
111
97


3
89
91
112
27


4
76
85
93
2


5
88
97
100
34


6
92
93
106
30


7
69
84
101
15


8
91
95
103
42


9
80
88
90
20


10
89
96
101
35


11
7
1
3
−11


12
68
101
103
45


13
76
94
105
38


14
75
90
100
38


15
72
93
104
45


16
85
105
99
37


17
95
105
99
34


18
58
92
98
3


19
54
69
90
12


20
91
68
88
13


21
17
−7
6
6


22
1
−14
−7
0


23
17
42
25
4


24
85
100
99
41


25
96
100
104
43


26
94
99
104
65


27
95
98
100
58


28
94
96
103
67


29
71
101
101
67


30
89
99
100
53


31
6
31
23
4


32
4
39
22
−1


33
99
97
103
35


34
100
94
110
90


35
96
93
112
50


36
95
96
101
34


37
14
68
70
9


38
38
77
83
21


39
99
98
105
66


40
64
96
101
46


41
75
95
104
34


42
73
87
107
8


43
70
78
107
4


44
10
1
12
−8


45
1
−9
9
−6


46
88
100
107
79


47
97
97
105
45


48
95
98
103
31


49
71
96
106
32


50
84
94
102
34


51
85
98
103
30


52
91
97
103
20


53
13
1
3
2


54
−1
5
1
6


55
8
12
7
6


56
83
95
91
62


57
−7
−1
87
10


58
88
95
10
47


59
73
89
9
20


60
−1
7
53
−9


61
−5
23
103
1


62
12
11
98
7


63
77
96
73
61


67
90
102
99
50


68
93
99
100
40


69
−5
8
−4
−2


72
17
−6
7
−18


73
1
28
21
−14


74
17
19
27
−2


75
7
7
21
2


76
37
7
31
0


77
81
85
113
16


78
102
83
111
58


79
−6
17
20
−7


82
96
96
91
90


83
93
99
113
61


152
47
93
88
3


154



33


155



38


157



24


158
98
99
109
65


160



17


174
89
101
105
34


176



23


177



25


179



23


180
98
99
103
62


182



19


224
19
8
−6
−2


225
34
0
13
3


226
83
93
102
37


227
73
70
98
5


228
98
102
110
73


229
97
100
103
68


230
97
102
99
48


232
29
90
39
8


233
96
97
100
73


234
97
98
100
71


235
95
95
98
42


236
94
89
103
34


237
70
98
93
50


238
30
98
103
7


239
28
93
107
9


240



57


241



37


242



69


243



32


244



43


245



16


246



14


247



8


248



81


249



35


250



15


251



35


252



19


253



55


281
75
92
99
40


282
67
95
102
1


283



12


284



11


285
89
91
75
21









Example B5
Determination of the Ability of Compounds of the Invention to Bind a Serotonin Receptor
Serotonin (5-Hydroxytryptamine) 5-HT1A 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT1A receptor expressed in Chinese hamster ovary (CHO-K1) cells (Martin G R and Humphrey P P A. Neuropharmacol. 33:261, 1994; May J A, et al. J Pharmacol Exp Ther. 306(1): 301, 2003) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mM MgSO4) is used. Compounds of invention are incubated with 1.5 nM [3H]8-OH-DPAT for 60 min. at 25° C. Non-specific binding is estimated in the presence of 10 μM Metergoline. Receptor proteins are filtered and washed, the filters are then counted to determine [3H]8-OH-DPAT specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT1B 
To evaluate in radioligand binding assays the activity of compounds of the invention, serotonin (5-Hydroxytryptamine) 5-HT1B receptor from Wistar Rat cerebral cortex (Hoyer et al. Eur J. Pharmaco. 118: 1, 1985; Pazos et al. Eur J. Pharmacol. 106: 531, 1985) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline, 30 μM Isoprenaline) is used. Compounds of invention are incubated with 10 pM [125I]Cyanopindolol for 90 min. at 37° C. Non-specific binding is estimated in the presence of 10 μM Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [125I]Cyanopindolol specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT2A 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT2A receptor expressed in Chinese hamster ovary (CHO-K1) cells (Bonhaus, D. W. et al. Br. J. Pharmacol. 115:622, 1995; Saucier, C. and Albert, P. R., J. Neurochem. 68:1998, 1997) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM [3H]Ketanserin for 60 min. at 25° C. Non-specific binding was estimated in the presence of 1 μM Mianserin. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Ketanserin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 6.
Serotonin (5-Hydroxytryptamine) 5-HT2B 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT2B receptor expressed in Chinese hamster ovary (CHO-K1) cells (Bonhaus, D. W. et al., Br. J. Pharmacol. 115:622, 1995) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl2, 0.1% Ascorbic Acid) is used. Compounds of invention are incubated with 1.2 nM [3H]Lysergic acid diethylamide (LSD) for 60 min. at 37° C. Non-specific binding is estimated in the presence of 10 μM Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [3H]LSD specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT2C 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT2C receptor expressed in Chinese hamster ovary (CHO-K1) cells (Wolf, W. A. and Schutz, J. S., J. Neurochem. 69:1449, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10 μM Pargyline) was used. Compounds of the invention were incubated with 1 nM [3H]Mesulergine for 60 min. at 25° C. Non-specific binding was estimated in the presence of 1 μM Mianserin. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Mesulergine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 6.
Serotonin (5-Hydroxytryptamine) 5-HT3 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT3 receptor expressed in human embryonic kidney (HEK-293) cells (Miller K et al. Synapase. 11:58, 1992; Boess F G et al. Neuropharmacology. 36:637, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1 mM EDTA, 5 mM MgCl2) is used. Compounds of invention are incubated with 0.69 nM [3H]GR-65630 for 60 min. at 25° C. Non-specific binding is estimated in the presence of 10 μM MDL-72222. Receptor proteins are filtered and washed, the filters are then counted to determine [3H]GR-65630 specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT4 
To evaluate in radioligand binding assays the activity of compounds of the invention, serotonin (5-Hydroxytryptamine) 5-HT4 receptor from Duncan Hartley derived Guinea pig striatum (Grossman C J et al. Br J. Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used. Compounds of invention are incubated with 0.7 nM [3H]GR-113808 for 30 min. at 25° C. Non-specific binding is estimated in the presence of 30 μM Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [3H]GR-113808 specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT5A 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT5A receptor expressed in Chinese hamster ovary (CHO-K1) cells (Rees, S. et al., FEBS Lett. 355:242, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 0.5 mM EDTA) is used. Compounds of the invention are incubated with 1.7 nM [3H]Lysergic acid diethylamide (LSD) for 60 min. at 37° C. Non-specific binding is estimated in the presence of 100 μM Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [3H]LSD specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
Serotonin (5-Hydroxytryptamine) 5-HT6 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT6 receptor expressed in human HeLa cells (Monsma, F. J. Jr. et al., Mol. Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compounds of the invention were incubated with 1.5 nM [3H]Lysergic acid diethylamide (LSD) for 120 min. at 37° C. Non-specific binding was estimated in the presence of 5 μM Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were then counted to determine [3H]LSD specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 6.
Serotonin (5-Hydroxytryptamine) 5-HT7 
To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT7 receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. L. et al., J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al., J. Biol. Chem. 268:18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 0.5 mM EDTA) is used. Compounds of invention are incubated with 5.5 nM [3H]Lysergic acid diethylamide (LSD) for 2 hours at 25° C. Non-specific binding is estimated in the presence of 10 μM Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [3H]LSD specifically bound. Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.







TABLE 6







Inhibition of ligand binding to aminergic G protein-coupled receptors


by compounds of the invention:










Comp
Serotonin (1 μM)












No.
5-HT2A
5-HT2C
5-HT6
















1
98
79
86



2
99
88
103



3
95
94
92



4
93
89
83



5
96
90
93



6
96
92
82



7
80
64
36



8
97
95
100



9
96
93
81



10
94
92
97



11
5
34
4



12
100
92
83



13
97
89
100



14
101
95
93



15
101
100
82



16
101
92
78



17
102
93
80



18
88
64
60



19
80
52
42



20
95
77
46



21
8
29
30



22
−2
−4
−12



23
67
37
17



24
98
95
99



25
97
94
93



26
100
93
87



27
99
91
92



28
100
94
95



29
100
101
103



30
100
98
86



31
43
56
2



32
60
48
4



33
100
86
98



34
98
97
103



35
99
91
102



36
97
83
99



37
91
85
12



38
96
98
41



39
98
97
103



40
97
97
101



41
99
99
101



42
95
101
73



43
93
91
48



44
17
41
1



45
22
16
2



46
100
98
98



47
99
98
77



48
97
98
73



49
97
98
88



50
98
95
88



51
97
98
94



52
97
96
84



53
41
32
−1



54
1
−2
−10



55
−2
32
4



56
97
95
104



57
10
65
−1



58
100
16
99



59
93
−3
97



60
−7
−5
3



61
43
89
5



62
12
101
−4



63
91
5
101



67
100
93
86



68
99
95
87



69
52
−1
−4



72
23
53
39



73
18
11
0



74
27
1
−4



75
34
13
−2



76
52
78
39



77
90
72
33



78
100
98
91



79
−8
−18
−7



82
98
98
104



83
99
100
103



152
100
94
73



154
100
99
92



155
99
98
101



157
98
101
78



158
101
99
93



160
94
103
99



174
102
101
100



176
99
99
74



177
98
99
96



179
98
100
77



180
101
100
95



182
101
102
96



224
−7
11
−4



225
38
44
16



226
92
82
36



227
85
66
30



228
99
97
104



229
100
98
102



230
97
96
100



232
70
93
20



233
102
100
103



234
101
98
103



235
102
98
97



236
101
100
102



237
99
100
103



238
103
100
86



239
102
97
59



240
98
97
102



241
100
97
100



242
99
94
102



243
98
102
99



244
100
101
103



245
99
99
97



246
98
99
94



247
98
99
74



248
99
101
103



249
100
98
101



250
100
99
99



251
101
99
99



252
96
87
98



253
102
101
103



281
100
98
97



282
98
103
71



283
90
100
40



284
94
100
42



285
100
99
94










Example B6
Determination of Serotonin (5-Hydroxytryptamine) 5-HT2A Agonist/Antagonist Activity of Compounds of the Invention
To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant serotonin 5-HT2A receptor expressed in human embryonic kidney (HEK-293) cells (Jerman J C, Brough S J, Gager T, Wood M, Coldwell M C, Smart D and Middlemiss D N. Eur J Pharmacol, 414: 23-30, 2001) is used. Cells are suspended in DMEM buffer, and distributed in microplates. A cytoplasmic calcium fluorescent indicator which varies proportionally to the free cytosolic Ca2+ ion concentration is mixed with probenecid in HBSS buffer complemented with 20 mM HEPES (pH 7.4), added into each well and equilibrated with the cells for 30 min. at 37° C. followed by 30 min. at 22° C.
To measure agonist effects, compounds of the invention, reference agonist or HBSS buffer (basal control) is added to the cells and changes in fluorescence intensity are measured using a microplate reader. For stimulated control measurements, 5-HT at 100 nM is added in separate assay wells.
The results are expressed as a percent of the control response to 100 nM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value is calculated.
To measure antagonist effects, the addition of the compounds of the invention, reference antagonist or HBSS buffer is followed by the addition of 3 nM 5-HT or HBSS buffer (basal control) prior the fluorescence measurements. The results are expressed as a percent inhibition of the control response to 3 nM 5-HT. The standard reference antagonist is ketanserin, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC50 value is calculated. Compounds are screened at 3 μM or lower, using DMSO as vehicle.
Example B7
Determination of Serotonin (5-Hydroxytryptamine) 5-HT6 Agonist/Antagonist Activity of Compounds of the Invention
To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant 5-HT6 receptor is transfected in CHO cells (Kohen, R., Metcalf, M. A., Khan, N., Druck, T., Huebner, K., Lachowicz, J. E., Meltzer, H. Y., Sibley, D. R., Roth, B. L. And Hamblin, M. W. Cloning, characterization and chromosomal localization of a human 5-HT6 serotonin receptor, J. Neurochem., 66: 47, 1996) and the activity of compounds of the invention is determined by measuring their effects on cAMP production using the Homogeneous Time Resolved Fluorescence (HTRF) detection method. Cells are suspended in HBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, and then distributed in microplates and incubated for 45 min. at 37° C. in the absence (control) or presence of compounds of the invention or the reference agonist or antagonist.
For agonist determinations, stimulated control measurement, separate assay wells contain 10 μM 5-HT. Following incubation, the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added. After 60 min. at RT, the fluorescence transfer is measured at lex=337 nm and lem=620 and 665 nm using a microplate reader. The cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).
The results are expressed as a percent of the control response to 10 μM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value is calculated.
For antagonist determinations, the reference agonist 5-HT is added at a final concentration of 100 nM. For basal control measurements, separate assay wells do not contain 5-HT. Following 45 min. incubation at 37° C., the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.
After 60 min. at RT, the fluorescence transfer is measured as mentioned above. The results are expressed as a percent inhibition of the control response to 100 nM 5-HT. The standard reference antagonist is methiothepin.
Example B8
Determination of Dopamine D2L Antagonist Activity of Compounds
To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant dopamine D2L receptor stably expressed in Chinese hamster ovary (CHO) cells (Senogles S E et al. J Biol. Chem. 265(8): 4507, 1990) is used. Compounds of invention are pre-incubated with the membranes (0.1 mg/mL) and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1 mM EDTA) for 20 min. and Scintillation Proximity Assay (SPA) beads are added for another 60 min. at 30° C. The reaction is initiated by 0.3 nM [35S]GTPγS for an additional 15 min. incubation period. Increase of [35S]GTPγS binding by 50 percent or more (350%) relative to the 1 mM dopamine response indicates possible dopamine D2L receptor agonist activity. Inhibition of a 10 μM dopamine-induced increase of [35S]GTPγS binding response by 50 percent or more (350%) indicates receptor antagonist activity. Compounds are screened at 3 μM or lower, using 0.4% DMSO as vehicle. Assay results are presented as the percent response of specific binding.
Example B9
Determination of Dopamine D2S Antagonist Activity of Compounds of the Invention
To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant dopamine D2S receptor stably expressed in Chinese hamster ovary (CHO) cells (Gilliland S L and Alper R H. Naunyn-Schmiedeberg's Archives of Pharmacology. 361: 498, 2000) is used. Compounds of invention are pre-incubated with the membranes (0.05 mg/mL) and 3 μM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1 mM EDTA) for 20 min. and Scintillation Proximity Assay (SPA) beads are then added for another 60 min. at 30° C. The reaction is initiated by 0.3 nM [35S]GTPγS for an additional 30 min. incubation period. Increase of [35S]GTPγS binding by 50 percent or more (350%) relative to the 100 μM dopamine response indicates possible dopamine D2S receptor agonist activity. Inhibition of a 3 μM dopamine-induced increase of [35S]GTPγS binding response by 50 percent or more (350%) indicates receptor antagonist activity. Compounds are screened at 3 μM or lower, using 0.4% DMSO as vehicle. Assay results are presented as the percent response of specific.
Example B10
Determination for Agonist or Antagonist Activity of Compounds of the Invention in a Histamine H1 Functional Assay
To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant Histamine H1 receptor expressed in human embryonic kidney (HEK-293) cells (Miller, T. R., Witte, D. G., Ireland, L. M., Kang, C. H., Roch, J. M., Masters, J. N., Esbenshade, T. A And Hancock, A. A. J. Biomol. Screen., 4: 249-258, 1999) is used. Cells are suspended in DMEM buffer, and then distributed in microplates. A cytoplasmic calcium fluorescent indicator which varies proportionally to the free cytosolic Ca2+ ion concentration is mixed with probenecid in HBSS buffer complemented with 20 mM HEPES (pH 7.4) and is then added into each well and equilibrated with the cells for 30 min. at 37° C. and then for another 30 min. at 22° C. To measure agonist effects, compounds of the invention, reference agonist or HBSS buffer (basal control) are added to the cells and changes in fluorescence intensity are measured using a microplate reader. For stimulated control measurements, histamine at 10 μM is added in separate assay wells.
The results are expressed as a percent of the control response to 10 μM histamine. The standard reference agonist is histamine, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value is calculated.
To measure antagonist effects, the addition of the compounds of the invention, reference antagonist or HBSS buffer is followed by the addition of 300 nM histamine or HBSS buffer (basal control) prior the fluorescence measurements. The results are expressed as percent inhibition of the control response to 300 nM histamine. The standard reference antagonist is ketanserin, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC50 value is calculated. Compounds are screened at 3 μM or lower, using DMSO as vehicle.
Example B11
Increase of Neurite Outgrowth of Neurons that were Cultured with Compounds of the Invention
Neurite Outgrowth in Cortical Neurons
Compounds are tested to determine their ability to stimulate neurite outgrowth of cortical neurons. Standard methods are used to isolate cortical neurons. For the isolation of primary rat cortical neurons, the fetal brain from a pregnant rat at 17 days of gestation is prepared in Leibovitz's medium (L15; Gibco). The cortex is dissected out, and the meninges are removed. Trypsin (Gibco) is used to dissociate cortical C with DNAse I. The cells are triturated for 30 min. with a pipette in Dulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal Bovine Serum (“FBS”) (Gibco) and centrifuged at 350×g for 10 min. at RT. The cells are suspended in Neurobasal medium supplemented with 2% B27 (Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at 30,000 cells per well of poly-L-lysine coated plates at 37° C. in 5% CO2-95% air atmosphere. After adhesion, a vehicle control or compounds of the invention are added at different concentrations to the medium. BDNF (50 ng/mL) is used as a positive control for neurite growth. After treatment, cultures are washed in phosphate-buffered saline (“PBS”; Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3 days growth. Several pictures ( ̃80) of cells with neurites are taken per condition with a camera. The length measurements are made by analysis of the pictures using software from Image-Pro Plus (France). The results are expressed as mean (s.e.m.). Statistical analysis of the data is performed using one way analysis of variance (ANOVA).
Neurite Outgrowth in Rat Mixed Cortical Cultures
Cortical mixed cultures are prepared from E18 Wistar rat embryos. The cortices are dissected out and the tissue was cut to small pieces. The cells are separated by 15-min. incubation with DNase and papain. The cells are collected by centrifugation (1500 rpm, 5 min.). The tissue is triturated with a pipette and the cells are plated using the micro-islet protocol (20 000 cells in 25 μl medium) on poly-L-lysine coated 48 wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin, 10% heat-inactivated fetal bovine serum (FBS-HI) and 10% heat-inactivated horse serum (HS-HI). After the cells has attached to the well, 250 μl medium is added to the wells. Four hours after plating the medium is changed to fresh medium (MEM with supplements and 5% HS-HI) containing test compound at 0.5, 5 and 50 nM concentrations. As positive controls BDNF (50, 100 and/or 150 ng/mL), and/or NGF (50 ng/mL and/or 100 ng/mL) are used. After 2 days in vitro, the cell's conditioned media are collected from plates before fixing the cells. The media samples are centrifuged 13 000 rpm 3 min. to get rid of cell debris. The samples are stored at −20 C for later analysis. Cells are formaldehyde-fixed and processed for immunocytochemistry. BDNF levels in the conditioned media are determined with a BDNF ELISA using the manufacturers (Promega, BDNF Emax® ImmunoAssay System, catalog number: G7610) instructions.
The cultures are fixed with 4% formaldehyde in 0.01 M PBS for 30 min. and washed once with PBS. The fixed cells are first permeabilized and non-specific binding is blocked by a 30-min. incubation with blocking buffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS. Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blocking buffer) is used as a primary antibody. The cells are incubated with the primary antibody for 48 h at +4° C., washed with PBS and incubated with secondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568 (1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositive cells are visualized by a fluorescence microscope equipped with appropriate filter set, and documented by a high resolution image capturing. The number of cells per field (4 field per well) are counted, and the neurite outgrowth is quantified using Image Pro Plus software.
The number of wells per compound concentration used is 6 (n=6). All data are presented as mean±standard deviation (SD) or standard error of mean (SEM), and differences are considered to be statistically significant at the p<0.05 level. Statistical analysis is performed using StatsDirect statistical software. Differences between group means are analyzed by using 1-way-ANOVA followed by Dunnet's test (comparison to the vehicle treated group).
Example B12
Use of an In Vivo Model to Evaluate the Ability of Compounds to Enhance Cognition, Learning and Memory in Scopolamine Treated Rats
The two-trial object recognition paradigm developed by Ennaceur and Delacour in the rat is used as a model of episodic/short term memory. Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. The paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement. The novel object recognition paradigm is sensitive to the effects of ageing and cholinergic dysfunction. See, e.g., Scali, C., et al., (1994), Neurosci. Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav. 53:277-283.
Male Sprague-Dawley rats between six and seven weeks old, weighing between 220-300 grams are obtained from Centre d'Elevage (Rue Janvier, B.P. 55, Le Genest-Saint-Isle 53940, France). The animals are housed in groups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm2) under standard conditions: at RT (22±2° C.), under a 12 hour light/12 hour dark cycle, with food and water provided ad libitum. Animals are permitted to acclimate to environmental conditions for at least 5 days before the experiment begins, and are numbered on their tails with indelible marker.
The experimental arena is a square wooden box (60 cm×60 cm×40 cm) painted dark blue, with 15 cm×15 cm black squares under a clear plexiglass floor. The arena and objects placed inside the arena are cleaned with water between each trial to eliminate any odor trails left by rats. The arena is placed in a dark room illuminated only by halogen lamps directed towards the ceiling in order to produce a uniformly dim light in the box of approximately 60 lux. The day before testing, animals are allowed to freely explore the experimental arena for three min. in the presence of two objects (habituation). Animals to be tested are placed in the experimental room at least 30 min. before testing.
Novel object recognition test is comprised of two trials separated by an interval of 120 min. or 24 h. When agents that disrupt memory such as the cholinergic antagonist scopolamine are used an inter-trial interval of 120 min. is preferred. Alternatively a 24 h inter-trial interval is used when studying effect of natural forgetting on novel object recognition task. During the first, or acquisition, trial (T1), rats are placed in the arena, where two identical objects have been previously placed. The time required for each animal to complete 15 seconds of object exploration is determined, with a cut-off time of four min. Exploration is considered to be directing the nose at a distance less than 2 centimeters (“cm”) from the object and/or touching the object. During the second, or testing, trial (T2), one of the objects presented in the first trial is replaced with an unknown or novel object, while the second, familiar object was left in place. Rats are placed back in the arena for three min., and exploration of both objects is determined. Locomotor activity of rats (number of times rats cross grid lines visible under the clear plexiglass floor) is scored for during T1 and T2. At the conclusion of the experiments, the rats are sacrificed by an overdose of pentobarbital given intraperitoneally.
The following parameters are measured as part of the novel object recognition task: (1) time required to achieve 15 seconds of object exploration during T1; (2) locomotor activity during T1 (number of crossed lines); (3) time spent in active exploration of the familiar object during T2 (TFamiliar); (4) time spent in active exploration of the novel object during T2 (TNovel); and (5) locomotor activity during T2 (number of crossed lines). The difference between time spent in active exploration of the novel object during T2 and time spent in active exploration of the familiar object during T2 (δ TNovel-TFamiliar) is evaluated. The % of animals in each group with TNovel-TFamiliar greater than or equal to 5 seconds is also derived; described as % of good learners.
Animals not meeting a minimal level of object exploration are excluded from the study as having naturally low levels of spontaneous exploration. Only rats exploring the objects for at least five seconds (TNovel+TFamiliar>5 seconds) are included in the study.
Animals are randomly assigned to groups of 14. Compounds of the invention and controls are administered to animals the groups as follows: Solutions of compounds are prepared freshly each day at a concentration of 0.25 mg/mL using purified water or saline as vehicle. Donepezil, used as a positive control, and scopolamine are administered simultaneously in a single solution of saline (5 mL/kg) prepared freshly each day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No. S-1875; St. Quentin Fallavier, France) is dissolved in saline to a concentration of 0.06 mg/mL.
Donepezil or its vehicle and scopolamine are administered intraperitoneally 40 min. before the acquisition trial (T1). Compounds or their vehicle are administered by gavage 25 min. before the acquisition trial (T1), i.e., 5 min. after administration of scopolamine. The volume of administration is 5 mL/kg body weight for compounds administered intraperitoneally, and 10 mL/kg for compounds administered orally. Recognition scores and % of good learners for compounds of the invention are determined.
Example B13
Use of an In Vivo Model to Determine the Ability of Compounds to Treat, Prevent and/or Delay the Onset and/or the Development of Schizophrenia in PCP Treated Animals
In vivo models of schizophrenia can be used to determine the ability of the compounds described herein to treat and/or prevent and/or delay the onset and/or the development of schizophrenia.
One exemplary model for testing the activity of one or more compounds described herein to treat and/or prevent and/or delay the onset and/or development of schizophrenia employs phencyclidine (PCP), which is administered to the animal (e.g., non-primate (rat) or primate (monkey)), resulting in dysfunctions similar to those seen in schizophrenic humans. See Jentsch et al., 1997, Science 277:953-955 and Piercey et al., 1988, Life Sci. 43(4):375-385). Standard experimental protocols may be employed in this or in other animal models. One protocol involves PCP-induced hyperactivity.
Male mice (various strains, e.g., C57Bl/6J) from appropriate vendor (for example, Jackson Laboratories (Bar Harbor, Me.) are used. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice/cage in OPTI mouse ventilated cages. All animals remained housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for at least two weeks prior to testing and are subsequently tested at an average age of 8 weeks. During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12/12 light/dark cycle. The room temperature is maintained between 20 and 23° C. with a relative humidity maintained between 30% and 70%. Food and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups.
The open filed (OF) test assesses locomotor behavior, i.e. to measure mouse locomotor activity at baseline and in response to pharmacological agents. The open field chambers are Plexiglas square chambers (27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeams (16×16×16) to measure horizontal and vertical activity. The analysis is configured to divide the open field into a center and periphery zone such that the infrared photobeams allow measurement of activity in the center and periphery of the field. Distance traveled is measured from horizontal beam breaks as the mouse moved whereas rearing activity is measured from vertical beam breaks.
Mice (10 to 12 animals per treatment group) are brought to the activity experimental room for at least 1 h acclimation to the experimental room conditions prior to testing. Eight animals are tested in each run. Mice are administered vehicle (e.g., 10% DMSO or 5% PEG200 and 1% Tween 80), compound of the invention, clozapine (positive control, 1 mg/kg ip) and placed in the OF chambers for 30 min. following which they are injected with either water or PCP and placed back in the OF chambers for a 60-min. session. At the end of each OF test session the OF chambers are thoroughly cleaned.
PCP Hyperactivity Mouse Model of Schizophrenia
The test compound at the desired dose is dissolved in appropriate vehicle, e.g., 5% PEG200, 1% Tween 80 and administered orally 30 min. prior to PCP injection. Clozapine (1 mg/kg) is dissolved in 10% DMSO and administered i.p. 30 min. prior to PCP injection. PCP (5 mg/kg) is dissolved in sterile injectable saline solution and administered i.p. Data are analyzed by analysis of variance (ANOVA) followed by post-hoc comparisons with Fisher Tests when appropriate. Baseline activity is measured during the first 30 min. of the test prior to PCP injection. PCP-induced activity is measured during the 60 min. following PCP injection. Statistical outliers that fell above or below 2 standard deviations from the mean are removed from the final analyses. An effect is considered significant if p<0.05. Total distances traveled and total rearing following PCP administration are compared between groups treated with compounds and groups treated with vehicle and positive control clozapine.
Example B14
Use of an In Vivo Model to Determine the Ability of Compounds to Treat, Prevent and/or Delay the Onset and/or the Development of Schizophrenia in Amphetamine Treated Animals
Male mice (various strains e.g., C57Bl/6J) from appropriate supplier (for example Jackson Laboratories, Bar Harbor, Me.) are used. Mice typically are received at 6-weeks of age. Mice are acclimated to the colony room for at least two weeks prior to testing. During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability and maintained on a 12/12 light/dark cycle. The room temperature is maintained between 20 and 23° C. with a relative humidity maintained between 30% and 70%. Food and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned between treatment groups.
The open field test (OF) is used to assess motor activity. The open field chambers are plexiglas square chambers (e.g., 27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeam sources (16×16×16). The enclosure is configured to split the open field into a center and periphery zone and the photocell beams are set to measure activity in the center and in the periphery of the OF chambers. Horizontal activity (distance traveled) and vertical activity (rearing) are measured from consecutive beam breaks.
On the day of testing, animals are brought to the experimental room for at least 1 h acclimation prior to start of treatment. Animals are administered with vehicle, haloperidol (positive control, 0.1 mg/kg ip) or test compound and placed in the OF. The time of administration of client compound to each animal is recorded. Baseline activity is recorded for 30 min. following which mice receive amphetamine (4 mg/kg) or water and are placed back in the OF chambers for a 60-min. session. At the end of each open field test session the OF chambers are thoroughly cleaned. Typically ten to twelve mice are tested in each group. Test compound doses typically range from 0.01 mg/kg to 60 mg/kg. Data are analyzed by analysis of variance (ANOVA) followed by post-hoc comparisons with Fisher Tests when appropriate. Baseline activity is measured during the first 30 min of the test prior to amphetamine injection. Amphetamine-induced activity is measured during the 60 min following amphetamine injection. Statistical outliers that fall above or below 2 standard deviations from the mean are removed from the final analyses. An effect is considered significant if p<0.05. Total distance traveled and total rearing following amphetamine administration are compared between groups treated with compound and groups treated with vehicle and positive control haloperidol.
Example B15
Use of the In Vivo Conditioned Avoidance Response (CAR) Model to Determine the Ability of Compounds to Treat, Prevent and/or Delay the Onset and/or the Development of Schizophrenia
All currently approved antipsychotic agents (typical and atypical) are known to have the ability to selectively suppress conditioned avoidance response (CAR) behavior in the rat. This evidence makes CAR one of the primary tests to assess antipsychotic activity of novel compounds. Rats (various strains, 2 months of age) are trained and tested in a computer-assisted, two-way active avoidance apparatus (shuttle box). This box consists of two compartments of equal size divided by a stainless steel partition containing an opening of 7×7 cm. Each compartment is equipped with an electrified grid floor made of stainless steel rods spaced 1 cm apart. Rats trained to avoid the foot shock are placed each day in the shuttle box for a 4 min. habituation period followed by 30 trials spaced by inter-trial interval varying at random between 20 and 30 sec. Each trial consists of a 10-sec. stimulus light (conditioned stimulus, CS) followed by a 10-sec. foot shock (unconditioned stimulus, US) in presence of the light presented in the compartment where the rat is located. If the animal leaves the compartment prior to the delivery of the foot shock, the response is considered an avoidance response. If the rat does not change compartment during the 10-sec. light period and during the 10-sec. shock+light period, an escape failure is recorded. This test requires animals to be trained 5 d/week. On each training day, rats are submitted to one training session of 30-trials. Treatment with test compound is initiated only when rats reach an avoidance performance of at least 80% on at least two consecutive training sessions. The test compound is administered orally at various doses and various pre-treatment times (depending upon specific pharmacokinetic properties).
Compounds with antipsychotic profile inhibit conditioned avoidance responses with or without increases in escape failures. Statistical analysis is performed using a Friedman two-way ANOVA by ranks followed by the Wilcoxon matched-pairs signed-ranks test to test each dose of the test compound administered versus vehicle control treated rats.
Example B16
An Animal Model of the Negative Symptoms of Schizophrenia: Subchronic PCP-Induced Social Interaction Deficits
Phencyclidine (PCP) administered to humans as well to experimental animals induces full-spectrum of schizophrenia symptoms, including negative symptoms and cognitive deficits. A major symptom of schizophrenia is considered to be social isolation/withdrawal as part of the cluster of negative symptoms. Subchronic treatment with PCP in rats leads to the development of clear signs of social withdrawal as measured by deficits in the interaction time with a cage intruder rat. Male Sprague Dawley rats (about 150 g, obtained from different vendors, for example Harlan, Ind.) are used in this study. Upon receipt, rats are group housed in OPTI rat ventilated cages. Rats are housed in groups of 2-3 per cage for the remainder of the study. During the period of acclimation, rats are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Rats are maintained on a 12/12 light/dark cycle with the light on at 7:00 a.m. The room temperature is maintained between 20-23° C. with a relative humidity maintained between 30-70%. Food and water are provided ad libitum for the duration of the study. Animals are randomly assigned across treatment groups and balanced by age.
For five days prior to test, rats are injected twice daily with either PCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 min pretreatment with vehicle, clozapine (2.5 mg/kg ip dissolved in 5% PEG:5% Tween 80) as positive control and test compound at desired dose dissolved in appropriate vehicle, a pair of rats, unfamiliar to each other, receiving the same treatment are placed in a white plexiglas open field arena (24′′×17′′×8′′) and allowed to interact with each other for 6 min. Social interactions (‘SI’) include: sniffing the other rat; grooming the other rat; climbing over or under or around the other rat; following the other rat; or exploring the ano-genital area of the other rat. Passive contact and aggressive contact are not considered a measure of social interaction. The time the rats spent interacting with each other during the 6 min. test is recorded by a trained observer. The social interaction chambers are thoroughly cleaned between the different rats. Data are analyzed by analysis of variance (ANOVA) followed by post-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effect is considered significant if p<0.05.
Example B17
An Animal Model of Extrapyramidal Syndrome (EPS): Measurement of Catalepsy in the Mouse Bar Test
Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) in animals and in humans. An animal model considered to be predictive of EPS is the mouse bar test, which measures cataleptic responses to pharmacological agents. Male mice (various strains) from appropriate vendor (for example, Jackson Laboratories (Bar Harbor, Me.) are used. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice per cage in OPTI mouse ventilated cages. All animals remain housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for at least two weeks prior to testing and are subsequently tested at an average age of 8 weeks. During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12/12 light/dark cycle. The room temperature is maintained between 20-23° C. with a relative humidity maintained between 30-70%. Food and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups.
In the mouse bar test, the front paws of a mouse are placed on a horizontal bar raised 2′′ above a Plexiglas platform and time is recorded for up to 30 sec. per trial. The test ends when the animal's front paws return to the platform or after 30 sec. The test is repeated 3 times and the average of 3 trials is recorded as index of catalepsy. In these studies the typical antipsychotic agent haloperidol (2 mg/kg ip dissolved in 10% DMSO) is used as positive control and induces rigidity and catalepsy as measured by time spent holding on the bar. 30 min. prior to the trial, test compound at desired dose and dissolved in appropriate vehicle is administered PO, vehicle and positive control haloperidol (2 mg·kg ip) are administered to separate groups of mice. Catalepsy responses are measure 30 min., 1 h and 3 h following treatments. A trained observer is measuring time spent holding onto the bar during the 30 sec. trial. Data are analyzed by analysis of variance (ANOVA) followed by post-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effect is considered significant if p<0.05.
Example B18
An Animal Model to Test the Anxiolytic Effects of Compounds Using the Elevated Plus Maze (EPM) Test
This study may be used to test the anxiolytic properties of compounds detailed herein using the elevated plus maze (EPM) test in C57Bl/6J mice.
Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Me.) are used for the open field study. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice/cage in OPTI mouse ventilated cages. All animals remain housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for approximately 2 week prior to testing and are subsequently tested at an average age of 8 weeks of age. During the period of acclimation, mice and rats are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12 h/12 h light/dark cycle. The room temperature is maintained between 20 and 23° C. with a relative humidity maintained between 30% and 70%. Chow and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups. All animals are euthanized after the completion of the study.
Compounds may be dissolved in 5% PEG200/H2O and administered orally at a dose volume of 10 mL/kg 30 min prior to test; 2) Diazepam (2.5 mg/kg) is dissolved in 45% hydroxypropyl-β-cyclodextrin and administered orally at a dose volume of 10 mL/kg 30 min prior to test.
The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder) consists of two closed arms (14.5 h×5 w×35 cm length) and two open arms (6 w×351 cm) forming a cross, with a square center platform (6×6 cm). All visible surfaces are made of black acrylic. Each arm of the maze is placed on a support column 56 cm above the floor. Antistatic black vinyl curtains (7′ tall) surround the EPM to make a 5′×5′′ enclosure. Animals are brought to acclimate to the experimental room at least 1 h before the test. Mice are placed in the center of the elevated plus maze facing the closed arm for a 5-min run. All animals are tested once. The time spent, distance traveled and entries in each arm are automatically recorded by a computer. The EPM is thoroughly cleaned after each mouse.
Data are analyzed using analysis of variance (ANOVA) followed by Fisher's LSD post hoc analysis when appropriate. An effect is considered significant if p<0.05.
All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

## Claims

1. A compound of formula (I):



where:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each m and q is independently 0 or 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, or is taken together with a geminal R8 to form a moiety of the formula —OCH2CH2O—, is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R8 to form a methylene or a substituted methylene, is taken together with a vicinal R8 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R8 to form a bond, provided (i) when an R8 is taken together with a vicinal R8 to form a bond, the geminal R8 is other than hydroxyl, and (ii) at least one of R8a, R8b, R8c, R8d, R8e and R8f is hydroxyl; and
Q is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;
or a salt or solvate thereof.

2. The compound of claim 1, wherein each R4 is independently H, halo, unsubstituted C1-C4 alkyl, C1-C4 perhaloalkyl or substituted or unsubstituted aryl.

3. The compound of claim 1, wherein R1 is H, substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aralkyl.

4. The compound of claim 1, wherein R1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

5. The compound of claim 1, wherein:
each R2a and R2b is independently H, unsubstituted C1-C8 alkyl, or halo, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety; and
each R3a and R3b is independently H, unsubstituted C1-C8 alkyl, or halo, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety.

6. The compound of claim 5, wherein each of R2a, R2b, R3a and R3b is H.

7. The compound of claim 1, wherein each R10a, R10b, R11a and R11b is independently H, bromo, methyl, or hydroxyl, or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl, or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl.

8. The compound of claim 1, wherein each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, or unsubstituted C1-C4alkyl, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety.

9. The compound of claim 1, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with the carbon to which it is attached and a geminal R8 to form a methylene or a substituted methylene.

10. The compound of claim 1, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is taken together with a vicinal R8 to form a bond.

11. The compound of claim 1, wherein q is 0 and m is 0 or 1.

12. The compound of claim 1, wherein:
R1 is substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl;
each R2a and R2b is independently H, methyl, or fluoro, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety;
each R3a and R3b is independently H or fluoro;
each R10a and R10b is independently H, fluoro or methyl, or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl; and
each R11a and R11b is independently H, fluoro or methyl, or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl.

13. The compound of claim 1, wherein Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

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

15. A kit comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 wherein the compound is selected from the group consisting of compounds J-2, J-13, J-14, J-15, J-18, J-23, J-25, and J-27:






or a salt thereof.