# Patent

## Title
Pyrido[3,4-B]indoles and methods of use

## Abstract

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[3,4-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a division of U.S. Non-provisional patent application Ser. No. 13/791,559, filed on Mar. 8, 2013, which is a continuation of U.S. Non-provisional patent application Ser. No. 12/889,323, filed on Sep. 23, 2010, which claims priority to U.S. Provisional Patent Application No. 61/245,147, filed Sep. 23, 2009, and U.S. Provisional Patent Application No. 61/245,260, 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, 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), depression 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., 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 and PCT/US2008/008121. 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
Hydrogenated pyrido[3,4-b]indoles are provided Compositions and kits comprising the compounds are also provided, as are methods of using and making the compounds. The compounds provided herein may 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.
In one aspect, the invention provides a compound of the formula (I):




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, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m, and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
and provided that:
(A) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety, provisions (a)-(d) apply: (a) when each X7, X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is H or methoxy, each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, (b) when each X7-X10 is CR4 where R4 is H, each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is other than dimethylamino, (c) when each X7-X10 is CR4 where R4 is H, q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than pyrrolidin-1-yl, and (d) when each X7-X10 is CR4 where R4 is H, each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(B) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and each X7-X10 is CR4 where R4 is H, provisions (f)-(k) apply: (f) when each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy moiety, (g) when each q, m and n is 1, each R8a, R8b, R8c, R8d, R8e and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl], and (k) when each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(C) when R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety and each X7-X10 is CR4 where R4 is H, R8(a-f), m, n, q and Q are not taken together to form a tert-butoxycarbonyl group;
or a pharmaceutically acceptable salt thereof.
In another variation, compounds of the formula (I) are as described as above, provided that provisions (A)-(C) above and/or any one or more (and in one variation all) of provisions (D), (E), (F) and (G) apply:
(D) when R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, each X7-X10 is CR4 and each of R2a, R2b, R3b and R10b is H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;
(E) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b, are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;
(F) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, each X7-X10 is CR4 and each of R2b, R3b, R10a and R10b is H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl; and
(G) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than cyano, or a pharmaceutically acceptable salt thereof.
In one variation of formula (I), provisions (A)-(C), (D), (F) and (G) apply. In one variation, when compounds are of the formula (I), provisions (D), (E) and (F) apply. In another variation, when compounds are of the formula (I), provisions (A), (B), (C), (D), (E), (F) and (G) apply.
In one variation, compounds of the formula (I) have one or more of the following structural features: (1) at least one of X7, X8, X9 and X10 is N; (2) at least one of the R8 moieties present is other than H (e.g., where q, m and n are each 1, at least one of R8a-R8f is other than H, such as when at least one of the R8 moieties is an alkyl, alkoxy or hydroxyl group); (3) Q is other than a substituted heteroaryl; and (4) R1 is a substituted or unsubstituted C1-C8 alkyl (such as methyl) or acyl.
In another aspect, the invention provides a compound of the formula (A):




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, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro, or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m and q are independently 0 or 1;

    
    
        each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
    
    


each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety;
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety,
or a pharmaceutically acceptable salt thereof.
In one variation, compounds of the formula (A) are provided, wherein any one or more (and in one variation all) of provisions (A)-(C) below apply:
(A) when R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxl, and/or (ii) Q is other than a substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy;
(B) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a, and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than a substituted heteroaryl, and/or (ii) at least one of R11 or R12 is alkoxy; and
(C) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than a substituted heteroaryl, and/or (ii) at least one of R11 or R12 is alkoxy;
or a pharmaceutically acceptable salt thereof.
The invention further provides a compound of the formula (II):




wherein:

R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl;
p is 1 or 2;
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;
m, and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a pharmaceutically acceptable salt thereof.
Also provided is a compound of the formula (B):




wherein:

R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl;
p is 1 or 2;
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;
m and q are independently 0 or 1;
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or is taken together with a geminal R8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy or acylamino;
or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound of the formula (I-1):




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, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro, or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
or a pharmaceutically acceptable salt thereof.
It is understood that variations and aspects that are described herein for one formula, but which are applicable to another formula, apply equally to the other formula the same as if each and every variation and aspect were specifically and individually listed. For example, where a particular description of moiety Q is provided for one formula, it is understood that the same description for Q may be applied to the other formulae provide herein, where applicable (e.g., where the other formulae allow for such Q moieties). In addition, any proviso or provision that is described for one formula may also be applied to another formula, where applicable. For example, provisions (A)-(G) of formula (I) in one aspect apply equally to formula (I-1) or any other formula detailed herein, where applicable, the same as if each provision were specifically and individually listed.
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.
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.
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: 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: α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, H1, H2 and H3. 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.
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.


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, a description referring to about X includes a description of X per se.
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 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 beneficial or desired results including clinical results. 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, 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, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia, ADHD, 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, ADHD, 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. Aβ 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 anther 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. A pharmaceutically acceptable salt intends ionic interactions and not a covalent bond. As such, an N-oxide is not considered a salt. 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 Jan; 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 CC) 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)—, 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—, 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 carbocyclic group having from 2 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, 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, 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. 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 and 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-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)a—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 trifluoroalkyl (—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-hetero aryl, —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 —CHR′—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, salts and solvates of the compounds described as histamine receptor modulators.
The invention embraces a compound of the formula (I):




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 or carbonylalkylenealkoxy, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
and provided that:
(A) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety, provisions (a)-(d) apply: (a) when each X7, X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is H or methoxy, each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, (b) when each X7-X10, is CR4 where R4 is H, each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is other than dimethylamino, (c) when each X7-X10 is CR4 where R4 is H, q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than pyrrolidin-1-yl, and (d) when each X7-X10 is CR4 where R4 is H, each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(B) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and each X7-X10 is CR4 where R4 is H, provisions (f)-(k) apply: (f) when each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R8a, R8b, R8c, R8d, R8e and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl] and (k) when each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(C) when R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety and each X7-X10 is CR4 where R4 is H, R8(a-f), m, n, q and Q are not taken together to form a tert-butoxycarbonyl group;
or a pharmaceutically acceptable salt thereof.
In another variation, compounds of the formula (I) are as described as above, provided that in addition to provisions (A)-(C), provisions (D), (E), (F) and (G) also apply:
(D) when R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy and/or (ii) Q is other than substituted heteroaryl;
(E) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b are H, H then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl; and
(F) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy and/or (ii) Q is other than substituted heteroaryl; and
(G) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than cyano.
In one variation, compounds of the formula (I) have one or more of the following structural features: (1) at least one of X7, X8, X9 and X10 is N; (2) at least one of the R8 moieties present is other than H (e.g., where q, m and n are each 1, at least one of R8a-R8f is other than H, such as when at least one of the R8 moieties is an alkyl, alkoxy or hydroxyl group); (3) Q is other than a substituted heteroaryl; and (4) R1 is a substituted or unsubstituted C1-C8 alkyl (such as methyl) or acyl. In a particular variation of formula (I), at least one of X7, X8, X9 and X10 is N and at least one of the R8 moieties present is other than H (e.g., hydroxyl or methyl). In another variation of formula (I), at least one of X7, X8, X9 and X10 is N and each of the R8 moieties present is H. In one variation of formula (I), X7, X8, X9 and X10 is N, Q is other than a substituted heteroaryl and the R8 moieties present are either all H or at least one of the R8 moieties present is other than H.
In one variation, compounds of the formula (I) are provided where at least one of R8(a-f) is a substituted C1-C8 alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In another variation of formula (I), at least one R3a and R3b is aryl. In a particular variation of formula (I), at least one of R3a and R3b is phenyl.
In another variation, compounds of the formula (I) are provided where provisions (ii) and (iii) do not apply, such that one of provisions (i) and (iv)-(vi) applies. In another variation, compounds of the formula (I) are provided where provision (ii) does not apply, and one of provisions (i) and (iii)-(vi) applies. In another variation, compounds of the formula (I) are provided where provision (iii) does not apply, and one of provisions (i), (ii) and (iv)-(vi) applies.
In one variation, compounds of the formula (I) are provided where provision (i) applies such that R1 and R2′′ are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety. In another variation, compounds of the formula (I) are provided where m is 0 and q is 1; X7, X8 and X10 are CR4 where R4 is H; X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo and provision (ii) applies such that R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In yet another variation, compounds of the formula (I) are provided where m is 0 and q is 1; X7, X8 and X10 are CR4 where R4 is H; X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo and provision (iii) applies such that R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In still another variation, compounds of the formula (I) are provided where provision (iv) applies such that R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety. In one variation, compounds of the formula (I) are provided where provision (v) applies such that R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In another variation, compounds of the formula (I) are provided where provision (vi) applies such that R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety. In any of provisions (i)-(v) in one variation a five member ring is provided by the provision, such as in provision (i) when R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety. In any of provisions (i)-(v) in one variation a five member ring is provided by the provision, such as in provision (i) when R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety.
Compounds of the formula (I) are provided where at least one of m and q is 1 and at least one of X7, X8, X9 and X10 is CR4 where R4 is other than H, such as when R4 is methyl or halo. In one aspect, compounds of the formula (I) are provided where at least one of m and q is 1, at least one of X7, X8, X9 and X10 is CR4 where R4 is other than H and R1 and R3a are taken together to form a propylene moiety. Compounds herein may also be of the formula (I) where X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo. In one such variation, X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo, m and q are both 0 and Q is a substituted or unsubstituted aryl such a phenyl. In another such variation, X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo and R1 and R3a are taken together to form a propylene moiety. In another such variation, X9 is CR4 where R4 is a substituted or unsubstituted alkyl or halo and R1 and R10a are taken together to form a propylene moiety. Compounds of the formula (I) are also provided where at least one of m and q is 0. In one aspect, compounds of the formula (I) are provided where m, q and n are each 1 and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino.
Also provided are methods of using compounds described herein, such as compounds of formula (I), in various therapeutic applications. Also provided are methods of using a compound of Formula (I-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 or carbonylalkylenealkoxy, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl; and
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety.
Compounds detailed herein, such as compounds of the formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, are described as new histamine receptor modulators. Compounds of the invention may also find use in treating neurodegenerative diseases.
In another variation, the invention embraces compounds detailed herein, such as compounds of the formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, or any variation herein, or a salt or solvate herein. In a particular variation, the invention embraces methods of using compounds detailed herein, such as compounds of the formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, or any variation herein, or a salt or solvate herein as detailed herein.
In one variation, the invention embraces compounds detailed herein, such as compounds of the formulae (I)-(VII), (I-1), (Ia)-(IIc), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, or any variation herein or a salt or solvate herein. In another variation, the invention embraces methods of using and administering compounds detailed herein, such as compounds of the formulae (I)-(VII), (I-1), (Ia)-(IIc), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, or any variation herein or a salt or solvate herein as detailed herein.
In one variation, this invention embraces compounds of formulae (Ia)-(Ih):










wherein X7, X8, X9, X10, R1, R2a, R3a, R3b, R8a, R8b, R8c, R8d, R8e, R8f, R10a, R10b, Q p, m and q, where present, are as defined for formula (I);
each R9 is independently 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 moiety;
s is an integer from 0 to 5; and
t is an integer from 0 to 4.
In one variation, compounds of formulae (Ia)-(Ih) are provided wherein for each formulae: (A) at least one of X7-X10 is N; IN and/or (B) at least one of the R8 moities where present (at least one of R8a, R8b, R8c, R8d, R8e and R8f) is hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In one such variation, compounds of the formula (Ia)-(Ie) and (Ig)-(Ih) are provided wherein for each formulae, at least one of X7-X10 is N and each R8 moiety present is H. In another variation, compounds of the formula (Ia)-(Ie) and (Ig)-(Ih) are provided wherein for each formulae, at least one of the R8 moities present (R8a, R8b, R8c, R8d, R8e and R8f) is hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In a particular variation, compounds of the formula (Ia)-(Ie) and (Ig)-(Ih) are provided wherein at least one of R8e and R8f is hydroxyl or methyl. Where at least one of R8e and R8f is hydroxyl or methyl, in one aspect, each X7-X10 is CR4. In another variation, compounds of the formula (Ia)-(Ie) and (Ig)-(Ih) are provided wherein R8e is hydroxyl and R8f is methyl.
In one variation, the invention embraces compounds of any one or more of formulae (Ib), (Ie), (Ii), (Ij) and (Ik):




wherein Q, X7, X8, X9, X10, R4, R1, R2a, R2b, R3a, R3b, R10a, R10b, R8c, R8d, R8e and R8f, where present, are as defined for formula (I); and
wherein each R9 is independently 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 moiety;
s is an integer from 0 to 5; and
t is an integer from 0 to 4.
In one variation, the invention embraces compounds of formula (Ii-1):




wherein X7, R1, R2a, R2b, R3a, R3b, R10a and R10b are as defined for formula (I);
R4 is halo (e.g., chloro) or alkyl (e.g., methyl), ethyl, i-propyl or t-butyl;
R8e and R8f independently H, OH or CH3; and
Q is a substituted or unsubstituted aryl or heteroaryl,
provided that: (i) when X7 is N, R8e and R8f are H; and (ii) when X7 is CR4 where R4 is H, R8e is OH and R8f is H or CH3. In one embodiment of formula (Ii-1), Q is a substituted or unsubstituted pyridyl.
In one variation of formula (Ii-1), R4 is halo. When R4 is halo, in one aspect it is chloro. In another variation of formula (Ii-1), R4 is a C1-C4 alkyl, such as methyl, ethyl, propyl or butyl. In a further variation of formula (Ii-1), R1 is H or a substituted or unsubstituted C1-C8alkyl (such as methyl).
In one variation, this invention embraces compounds of any one or more of formulae (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and (Ii-7):







wherein R1, R2a, R2b, R3a, R3b, R10a and R10b are as defined for formula (I);
R4 is halo (e.g., chloro) or alkyl (e.g., CH3, ethyl, i-propyl or t-butyl);
R9 is H or CH3; and
R8f is H or CH3.
In one variation of formulae (Ii-2)-(Ii-7), R4 is halo. When R4 is halo, in one aspect it is chloro. In another variation of formulae (Ii-2)-(Ii-7), R4 is a C1-C4 alkyl, such as methyl, ethyl, propyl or butyl. In a further variation of formulae (Ii-2)-(Ii-7), R1 is H or a substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (Ii-3) are described, provided that in one aspect, R2a and R3a are not taken together to form a methylene (—CH2—) moiety or ethylene (—CH2CH2—) and provided that R3a and R10a are not taken together to form an ethylene (—CH2CH2—) or propylene (—CH2CH2CH2—) moiety.
Although R9 of formulae (Ii-2), (Ii-3), (Ii-5) and (Ii-6) is attached to a specific position of the pyridyl group, in other embodiments, analogous structures are provided wherein R9 is attached to the pyridyl ring at any available carbon atom. Likewise, although R9 of formulae (Ii-4) and (Ii-7) may be attached at any available position of the pyridyl ring, in another embodiment, analogous independent structures are provided where R9 is individually attached to each such available position.
The invention also embraces compounds of formula (A):




or a salt or solvate thereof,
wherein:
R1, R2a, R2b, R3a, R3b, R10a, R10b, X7, X8, X9, X10, m and q are as defined for formula (I);
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety; and
each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or a pharmaceutically acceptable salt thereof.
In one variation, compounds of the formula (A) are provided, wherein provisions (A)-(C) below apply:
(A) when R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, then either (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy;
(B) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy; and
(C) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy;
or a pharmaceutically acceptable salt thereof.
In one variation, compounds of the formula (A) are provided where at least one of R8(a-f) is a substituted C1-C8 alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In another variation of formula (A), at least one R3a and R3b is aryl. In a particular variation of formula (A), at least one of R3a and R3b is phenyl.
In still another variation of formula (A), each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond.
In one variation, compounds of the formula (A) are provided where provision (i) applies such that R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety. In another variation, compounds of the formula (A) are provided where provision (ii) applies such that R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In yet another variation, compounds of the formula (A) are provided where provision (iii) applies such that R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In still another variation, compounds of the formula (A) are provided where provision (iv) applies such that R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety. In one variation, compounds of the formula (A) are provided where provision (v) applies such that R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety. In another variation, compounds of the formula (A) are provided where provision (vi) applies such that R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety. In any variation of formula (A) detailed herein, where applicable, in one aspect the formula is further defined by one or more of the following structural features: X7, X8 and X10 are each CR4 where R4 is H; X9 is CR4 where R4 is a substituted or unsubstituted C1-C8 alkyl or halo; q is 0 and m is 1; each R8a, R8BR8c and R8d, if present, is H; and at least one of R11 and R12 is a substituted or unsubstituted C1-C8alkyl.
In one variation of formula (A), R11 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C8 perhaloalkyl and R12 is H, h substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C8 perhaloalkyl, or is taken together with R11 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkenyl moiety.
The invention also embraces compounds of formulae (A1), (A2), (A3) and (A4):




wherein R1, R2a, R2b, R3a, R3b, R8a, R8b, R8c, R8d, R10a, R10b, R11, R12, X7, X8, X9, X10, Q, m and q are as defined for formula (A).
In one variation, compounds of formulae (A1), (A2), (A3) and (A4) are provided, wherein one or more (and in one variation all) of provisions (A)-(C) below apply:
(A) when R1a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy;
(B) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy; and
(C) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-d) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl, and/or (iii) at least one of R11 or R12 is alkoxy.
All variations referring to formulae (I) and (A), where applicable, may apply equally to any formulae provided herein, such as any of formulae (I-1), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (II)-(VII), (IIa)-(IIk), (IIi-1), (A1)-(A4), (B), (B1)-(B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4 the same as if each and every variation were specifically and individually listed.
In another variation, the invention embraces compounds of the formula (II):




wherein:
R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2;
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (II) are provided where at least one of R8(a-f) is a substituted C1-C8 alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety. In one aspect of formula (II), p is 1. In a particular aspect of formula (II), p is 1 and X7, X8 and X10 are CR4 where R4 is H. In one such aspect of formula (II), p is 1; X7, X8 and X10 are CR4 where R4 is H and X9 is CR4 where R4 is an unsubstituted C1-C8 alkyl, such as methyl, or a halo, such as chloro. In another variation of formula (II), p is 1; X7, X8 and X10 are CR4 where R4 is H; X9 is CR4 where R4 is an unsubstituted C1-C8 alkyl and q is 0. In another variation of formula (II), p is 1; q is 0; m is 1 and R8c and R8d are both H. In one variation of formula (II), p is 1; q is 0; m is 1; R8c and R8d are both H and R8e and R8f are independently H, hydroxyl, unsubstituted C1-C8alkyl, or are taken together with the carbon to which they are attached to form a an unsubstituted methylene or a carbonyl moiety. In one variation of formula (II), p is 1; q is 0; m is 1; R8e and R8f are both H and R8c and R8d are independently H, hydroxyl, unsubstituted C1-C8alkyl, or are taken together with the carbon to which they are attached to form a an unsubstituted methylene or a carbonyl moiety. In still another variation of formula (II), p is 1; q is 0; m is 1; R8e is taken together with R8c to form a bond and R8d and R8f are independently H, unsubstituted C1-C8alkyl, or are taken together to form a bond, thereby providing an acetylene moiety. In another aspect of formula (II), p is 2. In any variation detailed herein, where applicable, the compound is further defined by one or both of the following structural features: X7, X8 and X10 are CR4 where R4 is H and X9 is CR4 where R4 is an unsubstituted C1-C8 alkyl.
In one variation, this invention embraces compounds of formulae (IIa)-(IIh):










wherein X7, X8, X9, X10, R2b, R3a, R3b, R8a, R8b, R8c, R8d, R8e, R8f, R10a, R10b, Q, m, p and q are as defined for formula (II);

each R9 is independently 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 moiety;
s is an integer from 0 to 5; and
t is an integer from 0 to 4.
In one variation, the invention embraces compounds of any one or more of formulae (IIb), (IIe), (IIi), (IIj) and (IIk):




wherein Q, X7, X8, X9, X10, R4, R2b, R3a, R3b, R8c, R8d, R8e, R8f, and p, where present, are as defined for formula (II);

each R9 is independently 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 moiety;
s is an integer from 0 to 5; and
t is an integer from 0 to 4.
In one variation, this invention embraces compounds of formula (IIi-1):




wherein X7, R2b, R3a, R3b, R10a and R10b are as defined for formula (I);
R4 is halo (e.g., chloro) or alkyl (e.g., CH3, ethyl, i-propyl or t-butyl);
R8e and R8f are independently H, OH or CH3; and
Q is substituted or unsubstituted aryl or heteroaryl,
provided that: (i) when X7 is N, R8e and R8f are H; and (ii) when X7 is CR4 where R4 is H, R8e is OH and R8f is H or CH3. In one embodiment of formula (IIi-1), Q is a substituted or unsubstituted pyridyl.
In one variation of formula (IIi-1), R4 is halo. In another variation of formula (IIi-1), R4 is a C1-C4 alkyl.
The invention also embraces compounds of formulae (B):




or a salt or solvate thereof,

wherein:

R2b, R3a, R3b, R10a, R10b, X7, X8, X9, X10, m, p and q are as defined for formula (II);
each R8a, R8b, R8c and R8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety.
In one variation, compounds of the formula (B) are provided where at least one of R8(a-f) is a substituted C1-C8 alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In another variation of formula (B), each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond.
In another variation of formula (B), R11 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C8 perhaloalkyl and R12 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C8 perhaloalkyl, or is taken together with R11 and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkenyl moiety.
The invention also embraces compounds of formulae (B1), (B2), (B3) and (B4):




wherein R2b, R3a, R3b, R8a, R8b, R8c, R8d, R10a, R10b, R11, R12, X7, X8, X9, X10, Q V and p are as defined for formula (B).
In one variation of formula (B), m is 0 and q is 1. In another variation of formula (B), m is 0, q is 1 and at least one of R11 and R12 is an unsubstituted C1-C8 alkyl, such as methyl. In another variation of formula (B), m is 0, q is 1, R11 is H and R12 is H. In one aspect of formula (B), m is 0, q is 1, at least one of R11 and R12 is an unsubstituted C1-C8 alkyl and X7, X8 and X10 are each CR4 where R4 is H. In one aspect of formula (B), m is 0, q is 1, each of R11 and R12 is H and X7, X8 and X10 are each CR4 where R4 is H. In another aspect of formula (B), m is 0, q is 1, at least one of R11 and R12 is an unsubstituted C1-C8 alkyl, X7, X8 and X10 are each CR4 where R4 is H and X9 is CR4 where R4 is an unsubstituted C1-C8 alkyl. In another aspect of formula (B), m is 0, q is 1, R11 is H, R12 is H, X7, X8 and X10 are each CR4 where R4 is H and X9 is CR4 where R4 is an unsubstituted C1-C8 alkyl. In any variation of formula (B) detailed herein, where applicable, in one aspect Q is a substituted or unsubstituted aryl, such as phenyl or a mono- or di-halo substituted phenyl, or a substituted or unsubstituted heteroaryl, such as pyridyl or a methyl-substituted pyridyl. When Q is a pyridyl group it may be bound to the carbon bearing R8e and R8f at any available ring position (e.g. Q can be a 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.). The substituted aryl (e.g. substituted phenyl) or substituted heteroaryl (e.g. substituted pyridyl) in one aspect is substituted with 1 to 5 substituents independently selected from 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 and aminocarbonylamino moiety. In one such variation, Q is a phenyl or pyridyl substituted with at least one substituted or unsubstituted C1-C8 alkyl (e.g. methyl) or halo (e.g. fluoro) moiety. Q may also be substituted with a single moiety, e.g. 4-fluorophenyl or 6-methyl-3-pyridyl.
In one embodiment, the compound is of the formula (II) or (B) or any variation thereof detailed herein, where p is 1, each R2b, R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl or R3a and R3b are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety, and each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl. In another embodiment, the compound is of formula (II) or (B) or any variation thereof detailed herein, where p is 1, each R2b, R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl, and each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl.
In one embodiment, the compound is of the formula (II) or (B) or any variation thereof detailed herein, where p is 2, each R2b, R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl or R3a and R3b are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety, and each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl. In another embodiment, the compound is of the formula (II) or (B) or any variation thereof detailed herein, where p is 2, each R2b, R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl, and each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl.
In one variation, the compound is of the formula (II) where q, is 0; m and n are each 1; X7, X8 and X10 are each CR4 where R4 is H; and X9 is CR4 where R4 is H, halo or substituted or unsubstituted C1-C8 alkyl. In one such variation, the compound is further defined by Q being a substituted aryl or substituted heteroaryl and R8c, R8d, R8e and R8f each being H. In a further such variation, Q is a substituted phenyl or substituted pyridyl group. When Q is a pyridyl group it may be bound to the carbon bearing R8e and R8f at any available ring position (e.g. Q can be a 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.). The substituted aryl (e.g. substituted phenyl) or substituted heteroaryl (e.g. substituted pyridyl) in one aspect is substituted with 1 to 5 substituents independently selected from 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 and aminocarbonylamino moiety. In one such variation, Q is a phenyl or pyridyl substituted with at least one substituted or unsubstituted C1-C8 alkyl (e.g. methyl) or halo (e.g. fluoro) moiety. Q may also be substituted with a single moiety, e.g. 4-fluorophenyl or 6-methyl-3-pyridyl. In a particular variation, the compound is of the formula (II) where q is 0; m and n are each 1; R8c, R8d, R8e and R8f are each H; X7, X8 and X10 are each CR4 where R4 is H; X9 is CR4 where R4 is H, Cl or Me; and Q is a phenyl or pyridyl moiety substituted with a substituted or unsubstituted C1-C8 alkyl or halo group.
In another variation, the compound is of the formula (II) where q is 0; m and n are each 1; R8c, R8d, R8e and R8f are each H; X9 is CR4 where R4 is Cl; and R3a and R3b are each H or substituted or unsubstituted C1-C8 alkyl. In one such variation, the compound is further defined by Q being a substituted aryl or substituted heteroaryl. When Q is a substituted aryl or substituted heteroaryl, it may be a moiety as defined in the paragraph immediately above and include a phenyl or pyridyl group substituted with a substituted or unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., fluoro) group. In one such variation, one of R3a and R3b is a substituted or unsubstituted C1-C8 alkyl (e.g., a C1-C4 alkyl such as methyl or ethyl) and the other is H. In another such variation, R3a and R3b are both H. In one aspect, the compound is of the formula (II) where q is 0; m and n are each 1; R8c, R8d, R8e and R8f are each H; X7, X8 and X10 are each CR4 where R4 is H; and R3a and R3b are each H or unsubstituted C1-C8 alkyl.
In another variation, the compound is of the formula (II) where q is 0; m and n are each 1; R8c and R8d are each H; one of R8e and R8f is OH, C1-C8 alkyl, and the other of R8e and R8f is H, C1-C8 alkyl, or R8e and R8f are taken together form a cyclopropyl moiety, a methylenyl moiety or a carbonyl moiety. In a particular variation, the C1-C8 alkyl is a methyl group. In another variation, R2b, R3a, R3b, R10a and R10b are each H.
In another variation of formula (II), q is 0; m and n are each 1; R8c and R8d are each H; R8e and R8f are taken together to form a carbonyl moiety; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amino. In one particular variation, Q is phenyl. In another particular variation, Q is piperazin-4-yl, piperidin-4-yl, cyclohexylamino, morpholino or dimethylamino.
In another variation of formula (II), q is 0; m and n are each 1; R8c and R8d are taken together to form a carbonyl moiety; R8e and R8f are each H; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted amino. In one particular variation, Q is phenyl. In another particular variation, Q is piperazin-4-yl, piperidin-4-yl, cyclohexylamino, morpholino or dimethylamino.
In another variation, compounds of the formula (II) are provided, where q is 0; m and n are both 1; and R3a and R3b are both H. In one variation, the compound is further defined by applying one or more of (i)-(iv): (i) X9 is CR4 where R4 is halo (e.g., chloro), C1-C8 perhaloalkyl (e.g. CF3) or unsubstituted C1-C8 alkyl (e.g., methyl); (ii) R8c and R8d are taken together to form a carbonyl moiety; (iii) one of R8e and R8f is hydroxyl and the other is H or methyl; and (iv) Q is a substituted or unsubstituted phenyl. In one such variation, (i) and (ii) apply. In another variation, (i) and (ii) and (iv) apply. In a further variation, (i) and (iii) apply. In still a further variation, (i), (iii) and (iv) apply.
In another variation, the compound is of the formula (II) where q is 0; m and n are both 1; R3a and R3b are both H and Q comprises a phenyl or pyridyl moiety. In one such variation, Q is phenyl or substituted phenyl. In another such variation, Q is a phenyl substituted with one halo or one substituted or unsubstituted alkyl moiety. The phenyl may be substituted with one halo moiety such as fluoro or may be substituted with one substituted or unsubstituted alkyl moiety, e.g., a C1-C4 alkyl such as methyl. For example, in one variation, Q may be phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methylphenyl or 4-methylphenyl. In yet another variation, Q is a disubstituted phenyl wherein the phenyl is substituted with at least two moieties selected from halo and alkoxy. For example, in this variation, Q may be 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-fluoro-4-methoxyphenyl. In still another variation, Q is a substituted pyridyl moiety, such as 6-methyl-3-pyridyl. In a particular variation, the compound is of the formula (II) where q is 0; m and n are both 1; R3a and R3b are both H and Q is phenyl, phenyl substituted with one halo moiety or one alkyl moiety or substituted pyridyl. In a more particular variation, the compound of any of the these variations is further defined by one of R8c and R8d being taken together with one of R8e and R8f to form a bond and the R8c, R8d, R8e and R8f that are not taken to form a bond are H or methyl (thus providing an alkene moiety). In a particular such variation, R8c and R8d are taken together with one of R8e and R8f to form a bond and the R8c, R8d, R8e and R8f that are not taken to form a bond are H or methyl. In one aspect, the compound is of the formula (II) where q is 0; m and n are both 1; R3a and R3b are both H; one of R8c and R8d is taken together with one of R8e and R8f to form a bond and the R8c or R8d that is not taken to form a bond is H and the R8e or R8f that is not taken to form a bond is methyl. In a further such variation, the compound is of the formula (II) where q is 0; m and n are both 1; R3a and R3b are both H; Q comprises a phenyl or pyridyl moiety; one of R8c and R8d is taken together with one of R8e and R8f to form a bond and the R8c or R8d that is not taken to form a bond is H and the R8e or R8f that is not taken to form a bond is methyl.
In another variation, the compound is of the formula (II) where q is 0, m and n are both 1, R8c and R8d are taken together to form a carbonyl. In one such variation the compound is further defined by any one or more of (i)-(iv): (i) R8e and R8f are both H; (ii) Q is a substituted phenyl; (iii) X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl or halo; and (iv) one of R3a and R3b is substituted or unsubstituted C1-C8 alkyl, phenyl or H and the other is H. Where more than one (i)-(iv) applies, they may be combined in any manner, e.g., (i) and (ii); (i) and (iv); (ii), (iii) and (iv), (i), (ii), (iii) and (iv), etc. In one variation, Q is a phenyl substituted with a halo group, e.g., 2-fluorophenyl and 2-chlorophenyl. In one variation, X9 is CR4 where R4 is methyl or chloro. In a particular variation, the compound is of the formula (II) where q is 0, m and n are both 1, R8c and R8d are taken together to form a carbonyl; X9 is CR4 where R4 is methyl or chloro; and Q is a substituted phenyl.
In another variation, the compound is of the formula (II) where q is 0, m and n are each 1 and one of R8e and R8f is hydroxyl. In one such variation the compound is further defined by any one or more of (i)-(vi): (i) one of R8e and R8f is hydroxyl and the R8e or R8f that is not hydroxyl is methyl or H; (ii) X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro); (iii) X7, X8 and X10 are each CR4 where R4 is H; (iv) R2b is H; (v) R10a and R10b are both H; and (vi) Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl. In one such variation, (vi) applies and Q is an unsubstituted phenyl or phenyl substituted with a halo or substituted or unsubstituted C1-C8 alkyl group. Where more than one (i)-(vi) applies, they may be combined in any manner and/or number. For example, in one variation, all of (i)-(vi) apply and in another, any one or two or three or more of (i)-(iv) apply. In one variation, (ii) applies and X9 is CR4 where R4 is methyl or chloro. In another variation, both (ii) and (vi) apply, and in a particular aspect, X9 is CR4 where R4 is methyl or chloro and Q is phenyl or 2- or 4-substituted phenyl wherein the substituent is methyl or fluoro. In a particular variation, the compound is of the formula (II) where q is 0, m and n are each 1, one of R8e and R8f is hydroxyl and the other is H or methyl and Q is phenyl or a phenyl substituted with a halo or substituted or unsubstituted alkyl moiety.
In another variation, the compound is of the formula (II) wherein m and n are both 1 and Q is a substituted phenyl. In one such variation, q is also 1. In another such variation, q is 0. When Q is a substituted phenyl, the substituent or substituents may be positioned at any available phenyl ring position. For example, singly- or mono-substituted phenyl groups may be substituted at the ortho, meta or para-position of the phenyl group. Any available phenyl ring substitution pattern is suitable for di- or tri-substituted phenyl groups (e.g., at the ortho and para positions, at two ortho positions, at two meta positions, at the meta and para positions, at the ortho, meta and para positions, at two ortho and the para position, at two ortho and a meta position, or at two meta and a para or ortho position). In one aspect, Q is a mono-substituted phenyl wherein the substituent is halo or substituted or unsubstituted alkyl. In another aspect, Q is a di-substituted phenyl wherein both substituents are halo. In a further aspect, Q is a di-substituted phenyl wherein one substituent is halo and the other substituent is alkoxy. Q in one variation is a phenyl substituted with 1 to 5 moieties where each substituent 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 moiety. In another variation, Q is a phenyl substituted with at least one substituted or unsubstituted alkyl (e.g., methyl), alkoxy (e.g., methoxy) or halo (e.g., chloro or fluoro) moiety. In still another variation, Q is a phenyl substituted with at least two halo moieties, which may be the same or different. In another such variation, Q is a phenyl substituted with one halo moiety and one alkoxy moiety. Q in one variation is 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl or 3-fluoro-4-methoxyphenyl. In still another aspect, the compound is according to the foregoing variations wherein the compound is further defined by any one or more of (i)-(v): (i) X7, X8 and X10 are each CR4 where R4 is H; (ii) one of R8e and R8f is hydroxyl and the other is H or methyl; (iii) one of R8c and R8d is taken together with one of R8e and R8f to form a bond and the R8c or R8d that is not taken to form a bond is H and the R8e or R8f that is not taken to form a bond is a substituted or unsubstituted C1-C8 alkyl (e.g., methyl); (iv) q is 0; and (v) R3a and R3b are independently H, methyl, ethyl or phenyl. Where more than one (i)-(v) applies, they may be combined in any manner and/or number, provided that provisions (ii) and (iii) are not combined. For example, in one variation, all of (i)-(ii), (iv) and (v) apply and in another, any one or two or three or four or five of (i)-(v) apply provided that (ii) and (iii) are not combined.
In another variation, the compound is of the formula (II) wherein Q is a substituted 3-pyridyl (e.g., 6-methyl-3-pyridyl); m and n are each 1 and R8c, R8d, R8e, R8f are each H; R10a and R10b are both H. In one such variation, the compound is further defined by any one or more of: (i) X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl (e.g., methyl) or halo (e.g., chloro); (ii) X7, X8 and X10 are each CR4 where R4 is H; (iii) R3a and R3b are both H; and (iv) q is 0.
In another such variation, the compound is of the formula (IIh) and is further defined by any one or more of (i)-(viii), provided that only one of (ii), (iii) and (iv) applies: (i) q is 0; (ii) R8c and R8d are both H and R8e and R8f are independently H, hydroxyl or methyl; (iii) R8c is taken together with R8e to form a bond and R8d is taken together with R8f to form a bond, such that a triple bond exists between the carbons bearing such R8 groups; (iv) one of R8c and R8d is taken together with one of R8e and R8f to form a bond and the R8c or R8d that is not taken to form a bond is H and the R8e or R8f that is not taken to form a bond is H or methyl; (v) X9 is CR4 where R4 is halo (e.g., chloro) or substituted or unsubstituted C1-C8 alkyl (e.g., methyl); (vi) X7, X8 and X10 are each CR4 where R4 is H; (vii) R2b is H; and (viii) R10a and R10b are both H. Where more than one of (i)-(viii) applies, they may be combined in any manner and/or number, provided that only one of (ii), (iii) and (iv) applies. In a particular variation, the compound is of the formula (IIh), or a variation thereof where any one or more of (i)-(viii) applies (provided that only one of (ii), (iii) and (iv) applies), where R9 is halo, perhaloalkyl, alkoxy or a substituted or unsubstituted C1-C8 alkyl and s is an integer from 1 to 2.
In one such variation, the compound is of the formula (IIg) and is further defined by any one or more of (i)-(vi): (i) q is 0; (ii) m and q are each 1 and R8c, R8d, R8e and R8f are each H; (iii) X9 is CR4 where R4 is halo (e.g., chloro) or substituted or unsubstituted C1-C8 alkyl (e.g., methyl); (iv) X7, X8 and X10 are each CR4 where R4 is H; (v) R2b is H; and (vi) R10a and R10b are both H. Where more than one of (i)-(vi) apply, they may be combined in any manner and/or number. The pyridyl ring may be attached to the parent structure at any available position, e.g., the pyridyl may be a 2-pyridyl, 3-pyridyl or 4-pyridyl group. In addition, when t is greater than 0, the R9 substituents may be bound to the pyridyl ring at any ring position. In one instance, t is 1 and the pyridyl is a 3-pyridyl group where the R9 moiety is bound at any available ring position. In a particular variation, the compound is of the formula (IIg), or a variation thereof, including where any one or more of (i)-(vi) apply, where R9 is substituted or unsubstituted C1-C8 alkyl and t is an integer from 1 to 2. In a particular such variation, R9 is methyl and t is 1, e.g., to provide a 6-methyl-3-pyridyl.
In one variation, the compound is of any one of the formulae (A), (A1)-(A4), (B) and (B1)-(B4) where q is 0,  indicates an E double bond configuration, R11 is H and R12 is C1-C8 alkyl. In one variation, the compound is of any one of the formula (A), (A1)-(A4), (B) and (B1)-(B4) where q is 0,  indicates a Z double bond configuration, R11 is H and R12 is C1-C8 alkyl.
In one variation, the compound is of the formula (B) where Q is a phenyl or substituted phenyl. When Q is a substituted phenyl in one aspect it is substituted with 1 to 5 substituents. When Q is a substituted phenyl, the substituent or substituents may be positioned at any available phenyl ring position. For example, singly- or mono-substituted phenyl groups may be substituted at the ortho, meta or para-position of the phenyl group. Any available phenyl ring substitution pattern is suitable for di- or tri-substituted phenyl groups (e.g., at the ortho and para positions, at two ortho positions, at two meta positions, at the meta and para positions, at the ortho, meta and para positions, at two ortho and the para position, at two ortho and a meta position, or at two meta and a para or ortho position). In one aspect, Q is a mono-substituted phenyl wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl and 4-fluorophenyl). In another aspect, Q is a di-substituted phenyl wherein both substituents are halo (e.g., 3,4-difluorophenyl, 3,4-dichlorophenyl and 2,4-dichlorophenyl). In a further aspect, Q is a di-substituted phenyl wherein one substituent is halo and the other substituent is alkoxy (e.g., 3-fluoro-4-methoxyphenyl). In one variation, Q is unsubstituted phenyl. In still another aspect, the compound is according to the foregoing variations is further defined by any one or more of (i)-(x), provided that (iv) and (v) are not combined, (ii) and (vi) are not combined and (iii) and (vi) are not combined: (i) q and m are both 0; (ii) R11 is H; (iii) R12 is an unsubstituted alkyl (e.g., a C1-C8 alkyl such as methyl); (iv) one of R3a and R3b is methyl, ethyl or phenyl and the other is H; (v) R3a and R3b are both H; (vi) R11 and R12 are taken together to form a bond, thereby providing an acetylenyl moiety; (vii) X9 is CR4 where R4 is unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); (viii) X7, X8 and X10 are each CR4 where R4 is H; (ix) R2b is H; (x) R10a and R10b are both H. Where more than one (i)-(x) apply, they may be combined in any manner and/or number, provided that provisions (iv) and (v) are not combined, provisions (ii) and (vi) are not combined and provisions (iii) and (vi) are not combined. In a particular variation, provision (iii) applies (R12 is an unsubstituted alkyl) and the double bond of compound (B) is in the “E” configuration. In another variation, provision (iii) applies (R12 is an unsubstituted alkyl) and the double bond of compound (B) is in the “Z” configuration.
In a particular variation, the compound is of the formula (B) where Q is unsubstituted phenyl and R11 and R12 are both H. In a more particular variation, the compound is further defined by each of provisions (i)-(vi): (i) q and m are both 0; (ii) R3a and R3b are both H; (iii) X9 is CR4 where R4 is unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); (iv) X7, X8 and X10 are each CR4 where R4 is H; (v) R2b is H; and (vi) R10a and R10b are both H.
In a particular variation, the compound is of the formula (B) where Q is a substituted phenyl and R12 is methyl. In a more particular variation, the compound is further defined by each of provisions (i), (ii), (vii)-(x): (i) q and m are both 0; (ii) R11 is H; (vii) X9 is CR4 where R4 is unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); (viii) X7, X8 and X10 are each CR4 where R4 is H; (ix) R2b is H; and (x) R10a and R10b are both H. In an even more particular variation, the compound is of the formula (B) where Q is a substituted phenyl, R12 is methyl, each of provisions (i), (ii) and (vii)-(x) apply and provision (iv) also applies: (iv) one of R3a and R3b is methyl, ethyl or phenyl and the other is H. In still another particular variation, the compound is of the formula (IIi) where Q is a substituted phenyl, R12 is methyl, each of provisions (i), (ii) and (vii)-(x) apply and provision (v) also applies: (v) R3a and R3b are both H.
In one variation, the compound is of the formula (B4) where  indicates an E double bond configuration, R11 is H and R12 is C1-C8 alkyl. In one variation, the compound is of the formula (IIi) where  indicates a Z double bond configuration, R11 is H and R12 is C1-C8 alkyl.
In one variation, the compound is of the formula (B4) wherein Q is a substituted phenyl group, such as those described for formula (B) above, including but not limited to, mono-substituted phenyl wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl and 4-fluorophenyl) and di-substituted phenyl wherein both substituents are halo (e.g., 3,4-difluorophenyl, 3,4-dichlorophenyl and 2,4-dichlorophenyl) or when one substituent is halo and the other is alkoxy (e.g., 3-fluoro-4-methoxyphenyl). A compound of formula (B4) where Q is a substituted phenyl may be further defined by any one or more of (i)-(vi): (i) R11 is H; (ii) R12 is an unsubstituted alkyl (e.g., a C1-C8 alkyl such as methyl); (iii) X9 is CR4 where R4 is halo (e.g., chloro) or alkyl (e.g., methyl); (iv) X7, X8 and X10 are each CR4 where R4 is H; (v) R2b is H; and (vi) R10a and R10b are both H. Where more than one (i)-(vi) applies, they may be combined in any manner and/or number. In one variation, the compound is of the formula (B4) where Q is a substituted phenyl and all of provisions (i)-(vi) apply.
In a particular variation of formula (B4), R11 is H and Q is a substituted or unsubstituted aryl or heteroaryl e.g., a substituted or unsubstituted phenyl or pyridyl. In a more particular variation of formula (B4), R11 is H, R12 is H or methyl and Q is a substituted or unsubstituted aryl or heteroaryl. Examples of substituted or unsubstituted phenyl or pyridyl Q groups include, but are not limited to, 3-pyridyl, 4-pyridyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 4-methyl-3-pyridyl, 4-fluorophenyl and 2-methyl-5-pyrimidyl.
In one variation of (IIf), Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
In a particular variation of (IIf), Q is a substituted or unsubstituted aryl or heteroaryl, e.g., a substituted or unsubstituted phenyl or pyridyl. Examples of Q include, but are not limited to, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-pyridyl, 4-pyridyl, 4-trifluoromethyl-3-pyridyl and 4-methyl-3-pyridyl.
In a further variation of (IIf), Q is a substituted phenyl. In one aspect, the compound of formula (IIf) where Q is a substituted phenyl, including but not limited to, mono-substituted phenyl wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl and 4-fluorophenyl) and di-substituted phenyl wherein both substituents are halo (e.g., 3,4-difluorophenyl, 3,4-dichlorophenyl and 2,4-dichlorophenyl) or when one substituent is halo and the other is alkoxy (e.g., 3-fluoro-4-methoxyphenyl). The compound of formula (IIk) where Q is a substituted phenyl may be further defined by one or more of (i)-(v): (i) one of R3a and R3b is methyl, ethyl or phenyl and the other is H; (ii) X9 is CR4 where R4 is halo (e.g., chloro) or alkyl (e.g., methyl); (iii) X7, X8 and X10 are each CR4 where R4 is H; (iv) R2b is H; h and (v) R10a and R10b are both H. Where more than one (i)-(v) apply, they may be combined in any manner and/or number. In one variation, the compound is of the formula (IIf) where Q is a substituted phenyl and all of provisions (i)-(v) apply.
Any formula detailed herein, where applicable, in one variation has each R3a, R3b, R10a, R10b independently selected from H, hydroxyl, alkoxy or substituted or unsubstituted C1-C8 alkyl. It is understood that by “where applicable” it is intended that such R3a, R3b, R10a, R10b moieties be a variation if the formula encompasses such a structure.
All variations referring to formula (II), where applicable, may apply equally to any of formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa)-(IIk), (IIi-1), (A), (A1)-(A4), (B), (B1)-(B4) (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, the same as if each and every variation were specifically and individually listed.
The invention embraces compounds of the formula (III):




wherein:

each R2a and R2b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
R3b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2;
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (III) are provided, where provisions (A) and (B) apply:
(A) when p is 1, provisions (a)-(d) apply: (a) when each X7, X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is H or methoxy, each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, (b) when each X7-X10 is CR4 where R4 is H, each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is other than dimethylamino, (c) when each X7-X10 is CR4 where R4 is H, q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than pyrrolidin-1-yl, and (d) when each X7-X10 is CR4 where R4 is H, each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(B) when p is 2 and each X7-X10 is CR4 where R4 is H, provisions (f)-(l) apply: (f) when each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy moiety, (g) when each q, m and n is 1, each R8a, R8b, R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl], and (k) when each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy; (l) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than cyano.
In another variation, in one aspect compounds of the formula (III) are provided where when each of X7-X10 is CR4 and each of R2a, R2b, R3b, R10a and R10b is H, then at least one of R8(a-f) is hydroxyl or alkoxy.
In one variation, compounds of the formula (III) are provided where at least one of R8a-R8f is a substituted alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In some variations, the compound is of the formula (III) where p is 1, at least one of X7-X10 is other than CH and Q is other than phenyl. In another variation, the compound is of the formula (III) where p is 1 and Q is substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted heterocyclyl, unsubstituted amino, aminoacyl, acyloxy, carboxyl, aminocarbonylalkoxy or acylamino. In some variations, the compound is of the formula (III) where p is 2 and at least one of X7-X10 is other than CH. In another variation, the compound is of the formula (III) where p is 2 and Q is substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, acyloxy, or aminocarbonylalkoxy.
In some variations, the compound is of the formula (III) where p is 1, provisions (a)-(e) apply: (a) when each X7, X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is H or methoxy, each q and m is 0, n is 1, each R8e and R8f is H and Q is other than phenyl; (b) when each X7-X10 is CR4 where R4 is H, each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is other than dimethylamino; (c) when each X7-X10 is CR4 where R4 is H, q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than pyrrolidin-1-yl; (d) when each X7-X10 is CR4 where R4 is H, each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy; and (e) when each X7-X10 is CR4 where R4 is H and each q, m and n is 0, Q is other than carbonylalkoxy. In some variations, the compound is of the formula (III) where p is 2 and each X7-X10 is CR4 where R4 is H, provisions (f)-(k) apply: (f) when each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R8a, R8b, R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R8c and R8d is H and R8c and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl] and (k) when each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy.
In some variations, the compound is of the formula (III) where each X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b are H, and at least one of R8(a-f) is hydroxyl or alkoxy.
The invention embraces compounds of the formula (IV):




wherein:

each R2a and R2b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2;
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
R10b is H, halo, or a substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (IV) are provided where at least one of R8a-R8f is a substituted alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In some embodiments, the compound is of the formula (IV) where p is 1 and each X7-X10 is CR4 where R4 is H, R8(a-f), m, n, q and Q are taken together to form a moiety other than a tert-butoxycarbonyl group.
The invention embraces compounds of the formula (V):




wherein:

R1 is H, or substituted or unsubstituted C1-C8 alkyl;
R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
R3b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
each R10a and R10b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (V) are provided where at least one of R8a-R8f is a substituted alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In another variation, compounds of the formula (V) are provided where each X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, and at least one of R8(a-f) is hydroxyl or alkoxy.
The invention embraces compounds of the formula (VI):




wherein:

R1 is H, halo, or substituted or unsubstituted C1-C8 alkyl;
R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
R10b is H, halo, or a substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (VI) are provided where at least one of R8a-R8f is a substituted alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
The invention embraces compounds of the formula (VII):




wherein:

R1 is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R2a and R2b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
R3b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each X7, X8, X9 and X10 is independently N or CR4;
m and q are independently 0 or 1;
n is 1;
p is 1 or 2;
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, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl;
R10b is H, halo, or a substituted or unsubstituted C1-C8 alkyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
or a salt or solvate thereof. In one variation, each R4 is independently H, halo, or substituted or unsubstituted C1-C8 alkyl.
In one variation, compounds of the formula (VII) are provided where at least one of R8a—R8f is a substituted alkyl where the C1-C8 alkyl is substituted with a carbonylalkoxy, carboxyl or acylamino moiety.
In another variation, the compound is of the formula (VII) where each X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, and at least one of R8(a-f) is hydroxyl or alkoxy.
The invention also embraces any one or more compounds of the formulae (III-1), (IV-1), (V-1), (VI-1) and (VII-1):




wherein Q, X7, X8, X9, X10, R1, R2a, R2b, R3a, R3b, R10a, R10b, R8c, R8d, R8e, R8f, and p, where present, are as defined for formula (III), (IV), (V), (VI) and (VII) respectively. For example, for formula (III-1), Q, X7, X8, X9, X10, R2a, R2b, R3b, R10a, R10b, R8c, R8d, R8e, R8f, and p are as defined for formula (III).

In one aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein X7, X8 and X10 are CR4 where R4 is H. In another aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein each X7, X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is as defined for formula (III), (IV), (V), (VI) and (VII) respectively, and Q is a substituted or unsubstituted aryl or heteroaryl. In another aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein each X7, X8 and X10 is CR4 where R4 is H; X9 is CR4 where R4 is halo (e.g., chloro) or alkyl (e.g., CH3, ethyl, i-propyl or t-butyl); R8c is OH; R8d is H or CH3; each R8e and R8f is H, and Q is a substituted or unsubstituted aryl or heteroaryl.
In another aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein each X7, X8 and X10 is CR4 where R4 is H; X9 is CR4 where R4 is halo (e.g., chloro) or alkyl (e.g., CH3, ethyl, i-propyl or t-butyl); R8c is OH; R8d is H or CH3; each R8e and R8f is H, and Q is a substituted or unsubstituted pyridyl. In one variation of formula (V-1), (VI-1) and (VII-I), R1 is H or a substituted or unsubstituted C1-C8 alkyl.
In a further aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein each X8 and X10 is CR4 where R4 is H, X9 is CR4 where R4 is as defined for formula (III), (IV), (V), (VI) and (VII) respectively, and Q is a substituted or unsubstituted aryl or heteroaryl. In another aspect, the invention embraces compounds of the formula (III-1), (IV-1), (V-1), (VI-1) and (VII-1) wherein X7 is as defined for formulae (III), (IV), (V), (VI) and (VII) respectively; each X8 and X10 is CR4 where R4 is H; X9 is CR4 where R4 is halo (e.g., chloro) or alkyl (e.g., CH3, ethyl, i-propyl or t-butyl); R8c and R8c are independently H, OH or CH3; each R8e and R8f is H; and Q is a substituted or unsubstituted aryl or heteroaryl, provided that: (i) when X7 is N, R8c and R8d are H; and (ii) when X7 is CR4 where R4 is H, R8c is OH and R8d is H or CH3. In one such embodiment, Q is a substituted or unsubstituted pyridyl.
It is understood that variations detailed herein as being applicable to one formula apply equally to other formulae, where applicable, the same as if each and every variation where specifically and indivisually listed. Thus, in the variations detailed throughout, including the variations provided below, the variations apply to all formulae where applicable. By applicable, it is understood that the variation applies if the given formula allows for such a variation, e.g., by including a particular moiety in the genus structure or allowing for a particular combination of elements by its structure.
In one variation, the compound is of any of the foregoing formulae, such as any of formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1)-(Ii-7), (IIa-IIk), (IIi-1), (III-1)-(VII-1), (A), (A1)-(A4), (B) and (B1)-(B4), wherein, where applicable, R1 is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In another variation, the compound is of any of the foregoing formulae, where R1 is substituted or unsubstituted C1-C8 alkyl or acyl. In a further variation, the compound is of any of the foregoing formulae, where R1 is unsubstituted C1-C8 alkyl. Where applicable, any variation of the formulae detailed herein may in additional variations be further defined by the R1 moieties of this paragraph.
In a particular embodiment, the compound is of a formulae described herein, such as any of formulae (I)-(VII), (I-1), (Ia)-(Ik), (Ii-1)-(Ii-), (IIa-IIk), (IIi-1), (III-1)-(VII-1), (A), (A1)-(A4), (B) and (B1)-(B4), where X7, X8, X9 and X10 are CR4. In another embodiment, the compound is of a formula detailed herein, such as the formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where at least one of X7, X8, X9 and X10 is N. Another variation provides a compound of a formula herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4) where at least two of X7, X8, X9 and X10 are N. A further variation provides a compound of a formula herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where two of X7, X8, X9 and X10 are N and two of X7, X8, X9 and X10 are CR4. A compound of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where one of X7, X8, X9 and X10 is N and three of X7, X8, X9 and X10 are CR4 is also embraced by this invention.
In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), 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 (A); 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 aromatic moiety is substituted is a single R4 group, which in one variation is halo or unsubstituted C1-C8 alkyl. 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, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), 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 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 aromatic moiety is substituted with a single R4 group, which in one variation is halo or unsubstituted C1-C8 alkyl. 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, the compound is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where 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 still a further variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where X7, X8, X9 and X10 are taken together 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 still a further variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), are taken together provide an aromatic moiety selected from the following structures:




wherein R4 is as defined in formula (I) 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, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where X7, X8, X9 and X10 are taken together provide an aromatic moiety selected from the following structures:




Any formula detailed herein, where applicable, may in one variation have X7, X8, X9 and X10 taken together to provide an aromatic moiety detailed herein above. It is understood that by “where applicable” it is intended that in one variation such X7, X8, X9 and X10 groups are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein X7, X8, X9 and X10 groups are taken together provide a pyridyl moiety, then a pyridyl moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where X7, X8, X9 and X10 groups are taken together provide a pyridyl moiety.
In another embodiment, a compound of the invention is of the formula (I), wherein X7-X10 are as defined in formula (I) or as detailed in any variation herein, where applicable, 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 a formula detailed herein, such as a compound of formulae (I), (V)-(VII), (A) and (A1)-(A4), wherein X7-X10 are as defined in formula (I) or as detailed in any variation herein, where applicable, 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 a formula detailed herein, such as a compound of formulae (I), (V)-(VII), (A) and (A1)-(A4), wherein X7-X10 are as defined in formula (I) or as detailed in any variation herein, where applicable, 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.
The invention embraces a compound according to a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation thereof detailed herein, where R2a, R2b, R10a, R10b, R3a, R3b and p are taken together to form a moiety selected from the group consisting of the structures:




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 a formula detailed herein, such as a compound of formulae (I)-(VII), or any variation thereof detailed herein, where q, m, n, R8a, R8b, R8c, R8d, R8e and R8f are taken together to form a moiety selected from the group consisting of the structures:







It is understood that any formula detailed herein, where applicable, in one aspect has its q, m, n, R8a, R8b, R8c, R8d, R8e and R8f, where present, taken together to form a moiety detailed in this paragraph.
In a further variation and where applicable, a compound of the formulae detailed herein is provided where q, m, n, R8a, R8b, R8c, R8d, R8e and R8f are taken together to form a moiety of the formula:




When the above structures are applied to a formula detailed herein, such as a compound of formula (I)-(VII) or any variation thereof, it is understood that q, m, n, R8a, R8b, R8c, R8d, R8e and R8f where applicable are taken together to form the foregoing moieties, including but not limited to, the structures of this paragraph. Likewise, any formula detailed herein, where applicable, may in one variation have q, m, n, R8a, R8b, R8c, R8d, R8e and R8f, if present, taken together to form a moiety as detailed herein above, including but not limited to, the structures of this paragraph. It is understood that by “where applicable” it is intended that in one variation such q, m, n, R8a, R8b, R8c, R8d, R8e and R8f groups, if present, are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein q, m, n, R8a, R8b, R8c, R8d, R8e and R8f groups, if present, are taken together to provide a —CH2CH2— moiety, then a —CH2CH2— moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where q, m, n, R8a, R8b, R8c, R8d, R8e and R8f groups, if present, are taken together to provide a —CH2CH2— moiety.

The invention further embraces a compound according to a formula detailed herein, such as a compound of formulae (I)-(VII), or any variation thereof detailed herein, 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-C8perhaloalkyl, carboxyl or carbonylalkoxy:




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where each R4 is H. The invention also embraces compounds of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where each R4 is independently H, halo, methyl, perfluoromethyl or cyclopropyl.
The invention also embraces compounds of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of the invention is of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted heterocyclyl. In yet another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is an unsubstituted C3-C8 cycloalkyl or an unsubstituted heterocyclyl. In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 still another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




wherein each R9 is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, 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 a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), 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, 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 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 another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety of the structure:




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




In yet another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:







In yet another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




In yet another variation, a compound is of any formula detailed herein and, where applicable, Q is




In yet another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a 6-membered ring heteroaryl or substituted heteroaryl selected from the structures:







In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a phenyl or substituted phenyl selected from the structures:







In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a 5-membered ring heteroaryl or substituted heteroaryl selected from the structures:







In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a 5-membered ring substituted or unsubstituted cycloalkyl or heterocyclyl selected from the structures:




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a 6-membered ring substituted or unsubstituted cycloalkyl or heterocyclyl selected from the structures:




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino moiety. In a particular variation, Q is an unsubstituted amino. In another variation, Q is substituted amino of the formula —N(C1-C8alkyl)2 such as the moiety —N(Me)2. —N(CH3)(CH2CH3). In another variation, Q is a substituted amino of the formula —N(H)(cycloalkyl or substituted cycloalkyl), such as a moiety of the formula:




In another variation, Q is a substituted amino of the formula —N(H)(aryl or substituted aryl), such as a moiety of the formula:




In a particular variation, Q is an amino or substituted amino and R8e and R8f are taken together to form a carbonyl moiety. In yet another variation, Q is an acylamino moiety. In still another variation, Q is an acylamino moiety and R8e and R8f are both hydrogen.
In another variation, Q is an alkoxy group of the formula —O—C1-C8alkyl, such as the moiety —O—CH2CH3. In yet another variation, Q is an alkoxy group and R8e and R8f are taken together to form a carbonyl moiety. In still a further variation, Q is a carbonylalkoxy moiety. In yet another variation, Q is a carbonylalkoxy moiety and R8e and R8f are both hydrogen.
In still another variation, Q is an acyloxy, aminocarbonylalkoxy or acylamino moiety. In one variation, Q is an acyloxy, aminocarbonylalkoxy or acylamino moiety and R8e and R8f are both hydrogen.
In one variation, Q is a moiety selected from the structures:




The invention also embraces compounds of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is an aminoacyl moiety. In one variation, Q is an aminoacyl group where at least one of Ra and Rb is H, such as when Q is of the formula —NHC(O)Rb. In one variation, Q is an aminoacyl moiety selected from the group consisting of: —NHC(O)-heterocyclyl, —NHC(O)— substituted heterocyclyl, —NHC(O)-alkyl, —NHC(O)-cycloalkyl, —NHC(O)-alkaryl and —NHC(O)— substituted aryl. In another variation, Q is an aminoacyl moiety selected from the group consisting of: —NHC(O)—C5-C7heterocyclyl, —NHC(O)—C1-C6alkyl, —NHC(O)—C3-C7cycloalkyl, —NHC(O)—C1-C3alkaryl and —NHC(O)-substituted phenyl. In a particular variation, Q is a moiety of the formula:




In one variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is acyloxy.
In one variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is a carbonylalkoxy moiety. In one variation, Q is a carbonylalkoxy moiety of the formula —C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl. In one variation, Q is carbonylalkoxy moiety of the formula —C(O)—O—C1-C6alkyl. In a particular variation, Q is a carbonylalkoxy moiety of the formula —C(O)—O—C2H5. In one variation, Q is a carbonylalkoxy moiety selected from the group consisting of: —C(O)—O—C1-C10alkyl, —C(O)—O—C1-C3alkaryl, —C(O)—O—C1-C3substituted alkyl and —C(O)—OH. In another variation, Q is —C(O)—O—C1-C6alkyl. In a particular variation, Q is a moiety of the formula:




In yet another variation, a compound is of any formula detailed herein and, where applicable, Q is




In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is an aminocarbonylalkoxy moiety. In one variation, Q is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—Rb. In another variation, Q is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—Rb where Rb is a substituted alkyl group. In a particular variation, Q is a moiety of the formula —NH—C(O)—O—CH2—C(C1)3.
The invention also embraces compounds of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or any variation of the foregoing detailed herein, where Q is an acylamino moiety. In one variation, Q is an acylamino group where at least one of Ra and Rb is H, such as when Q is of the formula —C(O)N(H)(Rb). In another variation, Q is an acylamino group where both Ra and Rb alkyl. In one variation, Q is an acylamino moiety selected from the group consisting of: —C(O)N(H)(alkyl), —C(O)N(alkyl)2, —C(O)N(H)(alkaryl) and —C(O)N(H)(aryl). In another variation, Q is an acylamino moiety selected from the group consisting of: —C(O)N(H)2, —C(O)—N(H)(C1-C8alkyl), —C(O)N(C1-C6alkyl)2 and —C(O)N(H)(C1-C3alkaryl). In a particular variation, Q is a moiety of the formula:




Any formula detailed herein, where applicable, may in one variation have as Q the moieties detailed herein above. It is understood that by “where applicable” it is intended that such Q moieties be a variation if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein Q is a phenyl moiety, then a phenyl moiety is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where Q is a phenyl moiety.
In a further variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), where 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 another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), or any variation of the foregoing detailed herein, where q, m, n, Q and R8a-R8f are taken together to form a moiety of the structure:






















In another variation, a compound of the invention is of a formula detailed herein, such as a compound of formulae (I)-(VII), or any applicable variation of the foregoing detailed herein, where q, m, and n, Q, R8a-R8f, R11 and R12 where applicable are taken together to form a moiety of the structure:




In another variation, any formula detailed herein, where applicable, may in one variation have q, m, and n, Q, R8a-R8f, R11 and R12 where applicable taken together to form a moiety of the structure:




In one embodiment, the invention also embraces compounds of formula G-1




wherein:

R4 is methyl; R8c is H, hydroxyl, or methyl; or R8c and R8d are taken together to form a methylene moiety or an oxo moiety; R8d is H, or methyl; and
Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidyl; substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl or substituted amino.
In another embodiment, the invention also embraces compounds of formula G-2




wherein:

R4 is methyl; R13 is CH2 or oxo; and
Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidyl; substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl or substituted amino.
In another embodiment, the invention also embraces compounds of formula G-3




wherein:

R4 is methyl; R13 is CH2 or oxo; and
Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidyl; substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl or substituted amino.
In another embodiment, the invention embraces compounds of the formulae G-2 or G-3 (shown above) wherein R4 is methyl; R13 is CRxRy where Rx and Ry are independently H or alkyl; and Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidyl; substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl or substituted amino.
In another embodiment, the invention also embraces compounds of formula G-4




wherein:

R4 is methyl; R14 is H or methyl; and
Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidyl; substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl or substituted amino.
In one embodiment, the invention includes compounds of formulae (G-1), (G-2), (G-3) and (G-4) wherein Q is




Examples of compounds according to the invention are depicted in Table 1. 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 1







Representative Compounds According to the Invention.










Comp.




#
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.
Compounds of the invention, such as compounds of the formula (I), may be used in a method of modulating a histamine receptor.
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, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
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., D3L), 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, D2L, 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-HT6, 5-HT7, D2, 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, 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. In one variation, a compound of the invention shows activity in neurite outgrowth assays using primary neurons in culture. In another variation, 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. In one variation, a compound of the invention is 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, and 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, and in preclinical models of attention/impulsivity and executive function, and in preclinical models of attention/impulsivity and executive function, and further stimulates neurite outgrowth.
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, and in preclinical models of attention/impulsivity and executive function, and in preclinical models of attention/impulsivity and executive function, 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 and 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 of a ligand 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, α2B 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, 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. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α1D, α2A, α1D, 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 a dopamine receptor D2. 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 D2 and to serotonin receptor 5-HT2A. 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 retention 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 a 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. In one variation, a compound of the invention has binding profiles similar to compounds with antipsychotic activity. In another variation, a compound of the invention is 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. 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 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, cognitive disorder includes ADHD. 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, a neurotransmitter-mediated disorder includes 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, 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, 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 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, α2B, serotonin receptor 5-HT2A, 5-HT 6, 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 D2 receptor and a serotonin 5-HT2A 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 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 D2 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 D2 receptor and a serotonin 5-HT2A 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.
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 formulae (I)-(VII), (A), (A1)-(A4), (B) and (B1)-(B4), or a 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); ethyl acetate (EtOAc); room temperature (RT); retention factor (0).
General methods of preparing compounds according to the invention are depicted in exemplified methods below. Other compounds of the invention may be prepared by similar methods. For example, Scheme Ib is an exemplified synthesis of the method detailed in Scheme Ia but other compounds of the invention may be prepared by similar methods.
A method of synthesizing compounds of the invention is shown as General Methods 1-19.







The Schemes 1-6 and General Methods 1-18 exemplify the synthesis of compounds of Formulae (II), (IV) and (VI), through use of Pictet-Spingler′ ring-formation conditions.
General Method 1
Arylhydrazine hydrochloride (1 equiv) is mixed with triethylamine (3 equiv) and alkyl halide (1 equiv) at 25° C. The reaction mixture is stirred at RT for 1 h and subsequently heated at 90° C. until completion of the reaction as determined by TLC and LC-MS (approx for 16 h). Reaction mixture is concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organic layer is dried (Na2SO4) and concentrated to obtain crude product which is purified by column chromatography (silica gel, 100-200 mesh, eluent: EtOAc-hexanes gradient).
General Method 2
Arylhydrazine hydrochloride (1 equiv) is added to a vigorously stirred mixture of tetra-n-butylammonium chloride (0.05 equiv) in 50% aqueous sodium hydroxide (1 mL/mmol of arylhydrazine hydrochloride) followed by alkyl halide (1.1 equiv). The mixture is heated at 60° C. (oil bath temp.) for 6 h. After cooling to RT, water is added and the mixture is extracted with chloroform. The total extract is dried (sodium sulfate) and evaporated in vacuo to furnish crude product that is purified by column chromatography (silica gel, 100-200 mesh, eluent: eluent: EtOAc-hexanes gradient or DCM).
General Method 3
The hydrazine derivative (1 equiv) is converted into the corresponding HCl salt and dissolved in water. The appropriate acetal (1 equiv) is added and the mixture is heated at 0-90° C. for 3-6 h. The reaction mixture is cooled to RT, and saturated aqueous NaHCO3 is added. The product is extracted with EtOAc. Concentration of the combined organic layers under vacuum yields crude product that is purified by chromatography on silica gel to obtain the product.
General Method 4
A solution of appropriate tryptamine derivative (1 equiv), formaldehyde (1 equiv) in acetonitrile containing 5% TFA (8-10 mL/mmol) is stirred at reflux for 15 min.-2 h. The reaction mixture is cooled to 25° C., concentrated under reduced pressure and partitioned between EtOAc and satd. aqueous NaHCO3. The organic layer is dried over sodium sulfate, evaporated under reduced pressure and the residue is purified by silica gel chromatography to obtain the product.
General Method 5
A mixture of appropriate carboline derivative with side chain carboxylate ester (1 equiv) and NaOH (3N, 5 folds w/v) in ethanol (5 folds w/v) is stirred at 50° C. for 3 h after which it is cooled to RT and neutralized with conc. HCl. The solvent is removed under reduced pressure to obtain corresponding crude carboxylic acid. The resulting crude product is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient, and/or 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).
General Method 6
A mixture of appropriate carboline derivative with side chain carboxylic acid (1 equiv) is stirred with appropriate alcohol (1 equiv), EDCI-HCl (1 equiv) and triethylamine (1 equiv) in DCM for 12-16 h. The reaction mixture is evaporated under vacuo to obtain the crude ester that is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient, and/or 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).
General Method 7
A mixture of appropriate carboline derivative with side chain carboxylic acid (1 equiv) is stirred with appropriate amine (1 equiv), EDCI-HCl (1 equiv) and triethylamine (1 equiv) in DCM for 12-16 h. The reaction mixture is evaporated in vacuo to obtain the crude amide that is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient, and/or 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).
General Method 8
Carboline derivative (1 equiv), epoxide derivative (4-7.5 equiv) and NaH (3 equiv) are heated in DMF (3 mL/mmol) at 120° C. for 16 h. The contents are quenched by MeOH and evaporated to dryness. The resulting crude product is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient, and/or 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).
General Method 9
Appropriate carboline (1 equiv) is dissolved in NMP (0.6 mL/mmol). Powdered KOH (3.5 equiv) is added to this solution, and the reaction mixture is stirred for 10 min. at 25° C. Appropriate vinylpyridine derivative (1.1 equiv) is added and the reaction mixture is heated in sealed tube at 45° C. for 30 min. The reaction is monitored by LCMS. After this period, the reaction mixture is cooled to 25° C. and diluted with satd. aqueous NaCl (5 mL). The product is extracted with EtOAc. The combined organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient, and/or 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).
General Method 10
A solution of 4% aqueous sulfuric acid (5 mL) is heated to 50° C. over 30-60 min. Nitrogen is bubbled through the solution as it is heated to displace dissolved air. The hydrazine derivative (1 mmol) is added to the heated mixture, and the solid is allowed to dissolve. The appropriate acetal (1.2 mmol) is then added as a stream over 30 min., and this mixture is heated at reflux for 2 h. The reaction mixture is cooled to RT, and 30% aqueous ammonium hydroxide (0.5 mL) is added drop wise maintaining the temperature at 25-30° C. The product is extracted with EtOAc. Concentration of the combined organic layers under vacuum yield a crude product that is purified by chromatography on silica gel using EtOAc: ethanol: NH4OH 7:3:1.
General Method 11
A mixture of appropriate tryptamine derivative (1.0 mmol), formaldehyde (1.0 mmol) and TFA (0.15 mL) in acetonitrile (3 mL) is stirred at 25° C. for 20 h. The solution is quenched with saturated aqueous NaHCO3 solution. The organic layer is separated, washed with brine and dried with MgSO4. The solvent is removed under reduced pressure. Flash chromatography (10% CH3OH/DCM) allowed isolation of product as thick oil.







General Method 12

General method for the preparation of compounds using Scheme II, as exemplified for the synthesis of Compound A: A suitably substituted phenyl hydrazine is reacted with a 4 carbon protected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generate a substituted 3-(2-aminoethyl)indole. This 3-(pyrrolidin-2-yl)methyl indole can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions [Org. Lett. (2003), 5(1:43-46] to give an N-unsubstituted β-carboline. This β-carboline can then be reacted with aryl and/or heteroaryl groups bearing a vinyl substituent to install the side chain denoted by Q in synthetic scheme II.







General Method 13

General method for the preparation of compounds using Scheme III as exemplified for the synthesis of Compound B: A suitably substituted phenyl hydrazine is reacted with a 4 carbon protected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generate a substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) to give an N-unsubstituted β-carboline. This β-carboline can then be reacted with aryl and/or heteroaryl styrene oxides (carboline, aryl/heteroaryl oxide, NaH, DMF, 120° C.) to install the side chain denoted by Q in synthetic scheme III.







General Method 14

General method for the preparation of compounds using Scheme IV as exemplified for the synthesis of Compound C: A suitably substituted phenyl hydrazine is reacted with an alkyl halide bearing an ester functionality, followed by a reaction with a 4 carbon protected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generate a substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) to give an N-substituted β-carboline. This β-carboline is then treated with base to affect the hydrolysis of the ester functionality leading to the generation of a free acid. This acid can then be reacted with an alkyl, aryl and/or heteroaryl primary or secondary amine (carboline derivative with side chain carboxylic acid, appropriate primary or secondary amine, EDCI and triethylamine in DCM for 12-16 h) to install the side chain denoted by R2 and R3 in Scheme IV.







General Method 15
General method for the preparation of compounds using Scheme V as exemplified for the synthesis of Compound D: A suitably substituted phenyl hydrazine is reacted with an alkyl halide bearing an ester functionality, followed by a reaction with a 4 carbon protected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generate a substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) to give an N-substituted β-carboline. This β-carboline is then treated with base to affect the hydrolysis of the ester functionality leading to the generation of a free acid. This acid can then be reacted with an alkyl, aryl and/or heteroaryl primary alcohol (carboline derivative with side chain carboxylic acid, appropriate alcohol, EDCI and triethylamine in DCM for 12-16 h) to install the side chain denoted by R2 in Scheme V.
General Method 16
Appropriate carboline (1 equiv, 84 mg, 0.34 mmol) is dissolved in DMF (15 mL/mmol). To this solution is added CuI (10 mol %, 6 mg, 0.034 mmol), L-proline (20 mol %, 8 mg, 0.068 mmol), K3PO4 (2 equiv). The reaction mixture is stirred for 10 min. at RT followed by addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (1.2 equiv). The reaction mixture is heated at 80° C. for 18 h. Solvent is evaporated under reduced pressure, the residue is diluted with brine and extracted with EtOAc. Organic layer is dried over Na2SO4, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography.
General Method 17
Appropriate beta-carboline (1 equiv) is mixed with CuSO4.5H2O (20 mol %), 1,10-phenanthroline (0.4 equiv), K3PO4 (2 equiv) and appropriate vinyl bromide (1.1 equiv) in toluene (5 mL). The reaction mixture is purged with nitrogen and heated at 80° C. for 16 h. The reaction mixture is filtered through Celite and Celite bed is rinsed with DCM. Combined organic layer is concentrated under reduced pressure and the residue is purified by silica gel chromatography (100-200 mesh) eluting with 60-80% EtOAc in hexane to obtain the product.




General Method 18

General method for the preparation of compounds using Scheme VI as exemplified for the synthesis of Compound E: A suitably substituted indole is reacted with maleimide, followed by reduction with an appropriate reducing agent to generate a substituted 3-(3-pyrrolidinyl)indole. This 3-(3-pyrrolidinyl)indole can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) to give the bicyclo-β-carboline. This β-carboline can then be functionalized in an analogous manner to those steps provided for in the other General Methods described above, and in the Examples described in particular below, to install the side chain denoted by R2 in synthetic scheme VI.




General Method 19

Scheme 7 indicates the synthesis of the carboline moieties of compounds of Formulae (III), (V) and (VII), through use of Fischer-Indole conditions, well known to those in the art. In general, an appropriately substituted aryl hydrazine is condensed with the ketone to form the aryl hydrazone, which is heated in dilute acid to complete the cyclization and provide the carboline product. If necessary any isomers can be separated at this stage, or after the next step. The carbolines can then be substituted at the NH position using the conditions described in the General Methods above. The synthesis of the bicyclic ketone intermediates has been described by Bastable et al. [J. Chem. Soc. Perkin I (1981), 1346-1351]; King et al. [J. Med. Chem. (1993), 36:683-689]; and Mewshaw et al. [J. Med. Chem. (1993), 36:343-352], the experimental details therein are hereby incorporated by reference.
General Methods for HPLC Analysis
(1) Column: Phenomenex Gemini C18, 50 mm×4.6 mm; (2) Mobile Phase A: Acetonitrile, B: 10 mM Ammonium Acetate in Water; (3) Column Temp: 40° C.; (4) Flow Rate: 1 mL/min.; (5) Gradient: 20% A, 0.3 min. hold, 20% A to 90% A 0.3-4.0 min., 90% A hold 1 min., 5.03-7.00 min. 20% A.
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.
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 Carboline 1
(A) Preparation of 3-(5-methyl-1H-indol-3-yl) pyrrolidine-2,5-dione




5-Methyl indole (10 g, 76 mmol) and maleimide (7.4 g, 76 mmol) in 77 mL of glacial acetic acid was heated at 90° C. for 24 h. The reaction mixture was cooled to RT, and the acetic acid was evaporated under reduced pressure. The residue was suspended in diethyl ether and filtered to obtain solid product (7 g).
(B) Preparation of 5-methyl-3-(pyrrolidin-3-yl)-1H-indole




Lithium aluminum hydride (7.9 g, 200 mmol) in dry THF (380 mL) was stirred for 20 min. at RT under nitrogen atmosphere. 3-(5-Methyl-1H-indol-3-yl) pyrrolidine-2,5-dione (9.5 g, 41 mmol) was added portionwise and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, quenched with aqueous sodium sulfate, and filtered. The solid was rinsed with THF and the THF layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (25% MeOH/DCM/ammonia) to afford the title compound. Yield: 4.2 g, 49.2%.
(C) Preparation of Carboline 1




5-Methyl-3-(pyrrolidin-3-yl)-1H-indole (8.4 g, 42 mmol), formaldehyde (5.04 g, 168 mmol) and TFA (4.78 g, 42 mmol) were mixed in 252 mL ethanol and heated to reflux for 3 h. Methoxyamine hydrochloride (14.03 g, 168 mmol) and water (420 mL) were added to the reaction mixture, and the reaction mixture was heated to reflux for an additional 2 h. The solvent was evaporated to minimal volume. This residue was cooled to 0° C., basified with aqueous NaOH solution, and the product extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was stirred in acetonitrile and the resulting solid product was filtered. Yield: 6.4 g.
Example 2
Preparation of Compound No. 1
Tetra butyl ammonium bromide was dissolved in 50% aqueous sodium hydroxide and stirred for 10 min. at RT. Carboline 1 (0.1 g, 0.47 mmol) was added, and the reaction mixture was stirred for 10 min. at RT, followed by addition of 2-(trifluoromethyl)-5-vinylpyridine. The reaction mixture was stirred at 110° C. overnight and the reaction was monitored by TLC, LCMS. On completion, the reaction mixture was cooled to RT and the compound was extracted with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to yield the crude product, which was purified by column chromatography to get 95 mg of free base. 50 mg of free base was converted into oxalate salt by treatment of oxalic acid (1 equiv) in THF (30 mg).
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 6.50, purity, 93.08%, flow rate, 1.4 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 8.10-8.00 (m, 1H), 7.70-7.60 (m, 2H), 7.30-7.25 (s, 1H), 7.15-7.10 (d, 1H), 6.95-6.85 (d, 1H), 4.55-4.45 (d, 2H), 3.75-3.65 (m, 2H), 3.55-3.25 (m, 2H), 3.20-2.90 (m, 3H), 2.3 5-2.20 (m, 5H), 2.10-1.90 (m, 2H).
Example 3
Preparation of Compound No. 2
Sodium hydride (33 mg, 1.4 mmol) was dissolved in dimethylformamide (5 mL) and stirred for 10 min. Carboline 1 (0.1 g, 0.47 mmol) was added to it and the reaction mixture was stirred for 10 min. at RT, followed by the addition of 2-(4-fluorophenyl)-2-methyloxirane. The reaction mixture was stirred overnight at RT. The reaction was monitored by TLC and LCMS. On completion of reaction, the mixture was quenched by the addition of ice-water. The product was extracted into EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to yield the crude product. The crude product was purified by reverse phase chromatography to afford 100 mg of the title compound, which was converted into TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 6.15, purity, 98.60%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.8-10.65 (m, 1H), 7.65-7.55 (m, 1H), 7.50-7.45 (m, 1H), 7.40-7.30 (d, 1H), 7.30-7.15 (m, 2H), 7.0-6.8 0 (m, 2H), 5.8-5.5 (m, 1H), 4.70-4.55 (m, 1H), 4.45-4.35 (m, 1H), 4.15-4.00 (m, 1H), 3.80-3.70 (m, 2H), 3.50-3.25 (m, 2H), 3.20-3.05 (m, 2H), 2.35-2.25 (d, 3H), 2.10-1.95 (m, 2H), 1.50-1.35 (d, 3H).
Example 4
Preparation of Compound No. 3
Compound No. 2 (80 mg, 0.21 mmol) was dissolved in 5.6 mL of 25% sulfuric acid in water and stirred at 90° C. for 3 h. The reaction mixture was cooled to RT, basified with aq. NaOH solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified using reverse phase chromatography. Yield 15 mg as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 9.85, purity, 90.99%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.9-10.85 (m, 1H), 7.7-7.55 (m, 2H), 7.5-7.3 (m, 2H), 7.25-7.15 (t, 2H), 7.05-6.95 (d, 1H), 5.25-5.05, (m, 1H), 4.8-4.4 (m, 1H), 4.38-4.35 (s, 2H), 3.9-3.75 (m, 2H), 3.65-3.5 (m, 3H), 3.25-3.1 (m, 2H), 2.4-2.35 (s, 3H), 2.15-2.05 (m, 2H).
Example 5
Preparation of Compound No. 4
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in dimethylformamide (7.5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.70 mmol) was added, and the reaction mixture was stirred at RT for 10 min., followed by addition of 2-phenyloxirane (120 mg, 1.0 mmol). The reaction mixture was stirred at RT overnight. The reaction was monitored by TLC and LCMS. On completion of reaction, the mixture was quenched with ice water and the product extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get 60 mg of pure product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 5.81, purity, 97.11%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.7-10.6 (m, 1H), 7.5-7.25 (m, 7H), 7.05-6.90 (m, 1H), 4.9-4.7 (m, 2H), 4.5-4.45 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.7 (m, 2H), 3.25-3.05 (m, 3H), 2.45-2.40 (s, 3H), 2.15-2.0 (m, 2H).
Example 6
Preparation of Compound No. 5
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in dimethylformamide (7.5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.70 mmol) was added, and the reaction mixture was stirred for 10 min. 2-p-Tolyloxirane (134 mg, 1.0 mmol) was added and the mixture was stirred at RT overnight. The reaction was monitored by TLC and LCMS. On completion of reaction, the mixture was quenched with ice water, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get 68 mg of pure product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 6.11, purity, 95.70%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.75-10.7 (m, 1H), 7.5-7.3 (m, 2H), 7.25-7.1 (m, 4H), 7.05-6.95 (m, 1H), 5.75-5.65 (m, 1H), 4.85-4.65 (m, 2H), 4.45-4.40 (m, 1H), 4.25-4.05 (m, 2H), 3.85-3.65 (m, 2H), 3.25-2.95 (m, 3H), 2.4 (s, 3H), 2.3 (s, 3H), 2.15-2.0 (m, 2H).
Example 7
Preparation of Compound No. 6
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in dimethylformamide (7.5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.70 mmol) was added, and the reaction mixture was stirred for 10 min. 2-(3-Fluoro-4-methoxyphenyl)oxirane (168 mg, 1.0 mmol) was added and the mixture stirred at RT overnight. Reaction was monitored by TLC and LCMS. Reaction mixture was quenched with ice water, extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get 30 mg of pure product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 5.93, purity, 92.15%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.75-10.65 (m, 1H), 7.45-7.3 (m, 2H), 7.25-6.9 (m, 4H), 5.8-5.7 (m, 1H), 4.85-4.7 (m, 2H), 4.60-4.35 (m, 2H), 4.20-4.05 (m, 4H), 3.85 (s, 3H), 3.25-3.1 (m, 3H), 2.35 (s, 3H), 2.15-2.0 (m, 2H).
Example 8
Preparation of Compound No. 7
Sodium hydride (27 mg, 1.2 mmol) was washed with hexane for removal of oil and dried under vacuum. It was suspended in THF. To this mixture, carboline 1 (100 mg, 0.47 mmol) in THF was added dropwise at 0° C. The reaction mixture was stirred for 0.5 h at RT. A solution of 2-chloro-1-(piperidin-1-yl)ethanone (91 mg, 0.56 mmol) in THF was added dropwise to the reaction mixture, which was then stirred at RT for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-water. The THF was evaporated and aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography to give 17 mg of pure product, which was stirred with ethanolic HCl to yield the product as the HCl salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 8.05, purity, 93.33%, flow rate, 1 mL/min.
1H NMR (CD3OD, free base) δ (ppm) 7.39 (s, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 5.03 (s, 2H), 4.28-4.35 (m, 2H), 3.82-3.95 (m, 2H), 3.40-3.72 (m, 7H), 2.40 (s, 3H), 2.30-2.37 (m, 2H), 1.52-1.60 (m, 2H), 1.65-1.77 (m, 4H).
Example 9
Preparation of Compound No. 8
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in dimethylformamide (7.5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.70 mmol) was added, and the reaction mixture stirred for 10 min. 2-(3,4-Dimethoxyphenyl)oxirane (181 mg, 1.0 mmol) was added and stirred at RT overnight. The reaction was monitored by TLC and LCMS. On completion of reaction, the mixture was quenched with ice water, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to get 40 mg of pure product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 5.52, purity, 98.70%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.75-10.65 (m, 1H), 7.50-7.30 (m, 2H), 7.10-6.70 (m, 4H), 5.75-5.65 (m, 1H), 4.85-4.75 (m, 2H), 4.50-4.30 (m, 1H), 4.25-4.05 (m, 2H), 3.85-3.65 (m, 6H), 3.30-3.05 (m, 2H), 2.40 (s, 3H), 2.15-1.95 (m, 2H).
Example 10
Preparation of Compound No. 9
Tetra butyl ammonium bromide (7 mg, 0.023 mmol) was dissolved in 50% aqueous sodium hydroxide and stirred for 10 min. at RT. Carboline 1 (0.1 g, 0.47 mmol) was added to the reaction mixture and stirred for 10 min. at RT. 3-Fluoro-5-vinylpyridine (69 mg, 0.56 mmol) was added, and the reaction mixture stirred at 100° C. overnight. The reaction was monitored by TLC and LCMS. Upon completion of reaction, the mixture was cooled to RT and the compound was extracted with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the crude product, which was purified by reverse phase chromatography to give 15 mg of product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 5.51, purity, 95.02%, flow rate, 1.4 mL/min.
1H NMR (DMSO, TFA salt) δ (ppm) 10.9-10.8 (m, 1H), 8.50-8.45 (m, 1H), 8.15-8.10 (m, 1H), 7.65-7.55 (m, 1H), 7.40-7.30 (m, 2H), 7.05-6.90 (m, 1H), 4.75-4.65 (m, 2H), 4.40-4.20 (m, 2H), 3.95-3.40 (m, 2H), 3.35-3.15 (m, 1H), 3.10-3.00 (m, 2H), 2.44-2.25 (m, 5H), 2.15-2.00 (m, 2H).
Example 11
Preparation of Compound No. 10
To a solution of Compound 5 (60 mg, 0.17 mmol) in DCM (2 mL), triethylamine (0.036 mL, 0.26 mmol) was added and stirred for 10 min. Methane sulfonyl chloride (0.016 mL, 0.19 mmol) was added slowly at 0° C. and the mixture stirred at RT for 1.5 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. This crude product was dissolved in NMP (1.0 mL) followed by addition of KOH powder (48 mg, 0.86 mmol) to it at RT. The mixture was heated at 80° C. overnight. The reaction was monitored by LCMS. Inorganic material was removed by filtration, and the crude product was purified by reverse phase chromatography to afford 4 mg of product as TFA salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 7.08, purity, 91.89%, flow rate, 1.4 mL/min.
1H NMR (CD3OD, TFA salt) δ (ppm) 7.5-7.6 (m, 2H), 7.4-7.48 (m, 2H), 7.10-7.22 (m, 3H), 6.63 (d, 1H), 5.2 (d, 2H), 4.7 (d, 1H), 3.85-4.09 (m, 2H), 3.62-3.75 (m, 2H), 3.42-3.5 (m, 2H), 2.47 (s, 3H), 2.26 (s, 3H).
Example 12
Preparation of Compound No. 11
To a solution of Carboline 1 (0.1 g, 0.47 mmol) in 50% sodium hydroxide solution (5 mL), tetrabutylammonium bromide (8 mg, 0.024 mmol) was added followed by the addition of 2-vinylpyridine (0.062 mL, 0.57 mmol). The reaction mixture was stirred at 90° C. overnight. After completion of reaction (monitored by TLC and LCMS), EtOAc was added and the solution washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography. The pure product obtained was dissolved in ethanolic HCl and concentrated to afford 28 mg of HCl salt.
Analytical HPLC: YMC ODS A, 4.6×150 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in Acetonitrile, gradient, 5% to 95% B in 8 min., hold for 1.5 min., 95% to 5% B in 0.01 min., retention time (min.), 4.32, purity, 95.02%, flow rate, 1.4 mL/min.
1H NMR (CD3OD, HCl salt) δ (ppm) 8.64 (d, 1H), 8.43 (t, 1H), 7.84-7.95 (m, 2H), 7.36 (s, 1H), 7.0 (d, 1H), 6.92 (d, 1H), 5.10 (d, 2H), 4.70 (d, 1H), 4.42-4.69 (m, 1H), 3.90-4.00 (m, 1H), 3.8-3.85 (m, 1H), 3.70 (d, 1H), 3.40-3.65 (m, 3H), 2.42-2.55 (m, 1H), 2.40 (s, 3H), 2.20-2.35 (m, 1H).
Example 13
Preparation of Compound No. 12
Tetrabutylammonium bromide (38 mg, 0.012 mmol) was dissolved in 50% aqueous sodium hydroxide (10 mL) and the mixture stirred for 10 min. at RT. Carboline 1 (500 mg, 2.4 mmol) was added and the reaction mixture stirred for 10 min. at RT, followed by addition of 2-(6-methylpyridin-3-yl)ethyl methanesulfonate (608 mg, 2.8 mmol). The reaction mixture was stirred at 110° C. overnight. Reaction was monitored by TLC and LCMS. On completion of reaction, the mixture was cooled to RT and the compound extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. The crude product was purified by reverse phase chromatography to get TFA salt, which was converted to free base to afford 55 mg of title compound.
1H NMR (CDCl3, oxalate salt) δ (ppm) 7.57 (s, 1H), 7.36 (s, 1H), 7.25-7.10 (m, 4H), 4.05-4.00 (m, 4H), 3.88-3.82 (m, 1H), 3.73-3.68 (m, 1H), 3.50-3.40 (m, 2H), 3.24-3.19 (m, 1H), 3.10-2.95 (m, 2H), 2.69-2.63 (m, 1H), 2.50 (s, 3H), 2.48 (s, 3H), 2.37-2.26 (m, 2H).
Example 14
Preparation of Compound No. 13
A suspension of dimethylformamide (7.6 mL) and sodium hydride (60%) (62 mg, 1.55 mmol) was stirred for 1 h at RT. To this suspension, Carboline 1 (109 mg, 0.51 mmol) was added and the mixture stirred for 10 min. To the same suspension, 2-(3,4-dichloro-phenyl)-2-methyl oxirane (150 mg, 0.73 mmol) was added and the mixture allowed to stir overnight at RT. The reaction mixture was quenched with 10 mL of MeOH portionwise. The solvent was evaporated under vacuum, and the crude product purified by silica gel (100-200 mesh) column chromatography, with MeOH in DCM as the solvent system. The pure product was converted into the oxalate salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 9.57, 9.83, purity, 95.38%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.70 (m, 1H), 7.58-7.40 (m, 2H), 7.30 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.60 (s, 3H).
Example 15
Preparation of Compound No. 14
A suspension of dimethylformamide (7.6 mL) and sodium hydride (60%) (62 mg, 1.55 mmol) was stirred for 1 h at RT. To this suspension, Carboline 1 (109 mg, 0.51 mmol) was added and stirred for 10 min. To the same suspension, 2-(2,4-dichloro-phenyl-)2-methyl oxirane (150 mg, 0.73 mmol) was added and allowed to stir overnight at RT. The reaction was monitored by TLC. The reaction was quenched with 10 mL MeOH portionwise. The solvent was evaporated under vacuum, and the crude product purified by silica gel (100-200 mesh) column chromatography, with MeOH: DCM as the solvent system. The pure product was converted into the oxalate salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 10.52, 10.78, purity, 92.34%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.80 (d, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 6.98 (d, 1H), 6.82 (d, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.60 (s, 3H).
Example 16
Preparation of Compound No. 15
Sodium hydride (62 mg, 1.68 mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1 (131 mg, 0.617 mmol) was added and the reaction mixture was stirred at RT for 30 min. followed by addition of 2-(3,4-difluorophenyl)-2-methyloxirane (150 mg, 0.881 mmol). The reaction mixture was stirred at RT for 2 h. The reaction was quenched with MeOH, and the solvent was removed by evaporation. Water was added to the residue, and the product extracted with EtOAc. The combined organic layers were washed with water (3×), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography using 0-10% MeOH in DCM as eluent. The pure product was converted into oxalate salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 8.06, 8.28, purity, 89.35%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.60 (m, 1H), 7.40 (m, 3H), 6.98 (d, 1H), 6.82 (d, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.80 (s, 3H).
Example 17
Preparation of Compound No. 16
Sodium hydride (67.4 mg, 1.68 mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1 (119 mg, 0.6 mmol) was added and the reaction mixture was stirred at RT for 30 min. followed by addition of 2-(4-chlorophenyl)-2-methyloxirane (150 mg, 0.8 mmol). The reaction mixture was stirred at RT for 2 h. The reaction was quenched with MeOH, and the solvent was evaporated. Water was added to the residue and the product extracted with EtOAc. The combined organic layers were washed with water (3×), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography using 0-10% MeOH in DCM as eluent. The pure product was converted into oxalate salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 9.11, 9.34, purity, 99.85%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.60 (d, 1H), 7.40 (m, 2H), 7.30 (m, 2H), 6.98 (d, 1H), 6.82 (d, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.80 (s, 3H).
Example 18
Preparation of Compound No. 17
Sodium hydride (74 mg, 1.85 mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1 (130.9 mg, 0.88 mmol) was added to it and the reaction mixture was stirred at RT for 30 min. followed by addition of 2-(2,4-difluorophenyl)-2-methyloxirane (150 mg, 0.617 mmol). The reaction mixture was stirred at RT for 2 h. It was monitored by TLC and NMR. On completion, the reaction was quenched with MeOH, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the product extracted with EtOAc. The combined organic layers were washed with water (3×), dried over sodium sulfate and concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography using 0-10% MeOH in DCM as eluent. The pure product was converted into the HCl salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 8.87, 9.06, purity, 84.26%, flow rate, 1 mL/min.
1H NMR (DMSO, HCl salt) δ (ppm) 7.40-7.20 (m, 3H), 7.0 (m, 1H), 6.80 (m, 2H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.80 (s, 3H).
Example 19
Preparation of Compound No. 18
Sodium hydride (674 mg, 1.68 mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1 (119 mg, 0.6 mmol) was added and the reaction mixture was stirred at RT for 30 min., followed by addition of 2-(3-chloro-4-fluorophenyl)-2-methyloxirane (150 mg, 0.8 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH, then the solvent was evaporated. Water was added to the residue and the product extracted with EtOAc. The combined organic layers were washed with water (3×), dried over sodium sulfate concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography using 0-10% MeOH in DCM as eluent. The pure product was converted into its oxalate salt.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 10 mM Ammonium Acetate, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 13.65, 13.81, purity, 84.30%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.60-7.40 (m, 3H), 7.20 (m, 1H), 6.98 (d, 1H), 6.82 (d, 1H), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.50 (s, 3H).
Example 20
Preparation of Compound No. 19
Example 20a
Preparation of nitrile 19A




Carboline 1 (1 g, 47 mmol) was stirred in benzene (15 mL) and toluene (20 mL). To this solution acrylonitrile (1 mL, 2.25 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min. To this ice cold solution, 1 mL of Triton-B was added. The reaction mixture was stirred at RT for 4 h. The reaction was monitored by TLC (10% MeOH in DCM). The product was recrystallized from hexane and ether. The pure product was converted into its oxalate salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 5.49, purity, 98.33%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.42 (d, 1H), 7.38 (s, 1H), 6.98 (d, 1H), 4.90 (d, 1H), 4.58 (d, 1H), 4.30 (m, 2H), 3.80 (m, 2H), 3.25 (m, 3H), 2.90 (t, 2H), 2.40 (s, 3H), 2.30 (m, 1H), 2.08 (m, 1H).
Example 20b
Preparation of Thioamide 19B




Nitrile 19A (1.2 g, 4.5 mmol) in pyridine (60 mL) and triethylamine (5 mL) was saturated with H2S for 25 min. The reaction mixture was concentrated under vacuum after 72 h at ambient temperature. The reaction mixture was azeotroped with toluene (3×). The product was recrystallized from hexane and ether. The pure product was converted into its HCl salt.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 10 mM Ammonium Acetate, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 9.98, purity, 93.53%, flow rate, 1 mL/min.
1H NMR (DMSO, HCl salt) δ (ppm) 7.30 (m, 2H), 6.95 (d, 1H), 4.70 (d, 1H), 4.30 (m, 3H), 3.60 (m, 2H), 3.20 (m, 3H), 2.80 (m, 2H), 2.40 (s, 3H), 2.20 (m, 1H), 2.0 (m, 1H).
Example 20c
Preparation of Compound No. 19
Thioamide 19B (100 mg, 33 mmol) was added to 2-bromoacetophenone (72 mg, 36 mmol) followed by addition of 2 mL of ethanolic HCl. The reaction mixture was heated at 80° C. in a sealed vessel for 20 min. The mixture was basified with 1M NaOH solution and extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate and concentrated under reduced pressure to yield the crude product, which was purified by column chromatography (100-200 mesh) and 0-8% MeOH:EtOAc as eluent. The pure product was converted into the HCl salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 9.73, purity, 92.78%, flow rate, 1 mL/min.
1H NMR (CD3OD, HCl salt) δ (ppm) 7.80 (d, 2H), 7.75 (s, 1H), 7.40 (m, 4H), 7.30 (d, 1H), 7.0 (d, 1H), 5.10 (d, 2H), 4.60 (m, 2H), 4.0 (m, 4H), 3.60 (bs, 2H), 3.35 (m, 2H), 2.40 (s, 3H), 2.20 (m, 1H)
Example 21
Preparation of Compound No. 20
Sodium hydride (56 mg, 1.41 mmol) was added to dimethylformamide (7 mL) and stirred for 10 min. at RT. Carboline 1 (100 mg, 0.47 mmol) was added to it and the reaction mixture was stirred at RT for 30 min. 2-(p-Tolyl)methyloxirane (100 mg, 0.67 mmol) was added and the reaction mixture stirred at RT for 12 h. The reaction mixture was quenched with MeOH, then the solvent was evaporated under vacuum. Water was added to the residue and the product extracted with EtOAc. The combined organic layers were washed with water (3×), dried over sodium sulfate concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography using 0-10% MeOH in DCM as eluent. The pure product was converted into oxalate salt.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 10 mM Ammonium Acetate, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 12.85, 13.06, purity, 92.88%, flow rate, 1 mL/min.
1H NMR (CD3OD, oxalate salt) δ (ppm) 7.30 (m, 2H), 7.20 (m, 2H), 7.10 (m, 2H), 6.95 (m, 1H), 5.10 (d, 2H), 4.60 (m, 2H), 4.0 (m, 4H), 3.60 (bs, 2H), 3.35 (m, 2H), 2.40 (s, 3H), 2.30 (s, 3H,) 2.20 (m, 1H), 1.60 (s, 3H).
Example 22
Preparation of Compound No. 21
Sodium hydride (84 mg, 60%, 2.1 mmol) was suspended in 5 mL dimethylformamide. Carboline 1 (212 mg, 1 mmol) was added to it at RT followed by addition of 2-bromoacetophenone (218 mg, 1.1 mmol). The reaction mixture was stirred at RT for 4 h. The reaction was quenched by addition of ice-water and the product was extracted with EtOAc. The organic layer was dried over anhydrous sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (100-200 mesh, eluent: 0-4% MeOH in DCM gradient). The pure product was converted into the HCl salt.
Analytical HPLC: YMC polymer C18, 4.6×150 mm, 6 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 15 min., hold for 3 min., 90% to 10% B in 1 min., retention time (min.), 8.15, 8.40, purity, 78.46%, flow rate, 1 mL/min.
1H NMR (DMSO, HCl salt) δ (ppm) 8.20 (d, 1H), 7.80 (d, 1H), 7.70 (m, 1H), 7.60 (m, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.0 (d, 1H), 6.80 (d, 1H),), 4.70 (m, 2H), 4.42 (m, 2H), 4.10 (bs, 2H), 3.80 (m, 3H), 2.30 (s, 3H), 2.0 (m, 2H), 1.50 (s, 3H).
Example 23
Preparation of Compound No. 22
Carbinol Compound No. 2 (118 mg, 3.2 mmol) was dissolved in 9.7 mL of 25% sulfuric acid in water, and stirred at 90° C. for 2.5 h. The reaction mixture was cooled and basified with aqueous NaOH solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 10 mg of the desired product as free base. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in THF.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1 mL/min., Retention time, 10.335 min., HPLC purity, 99.34%.
1H NMR (DMSO, oxalate salt) δ (ppm) 10.88-10.85 (m, 1H), 7.68-7.60 (m, 2H), 7.45-7.40 (m, 2H), 7.30-7.20 (m, 2H), 7.02-6.95 (d, 1H), 5.35 (s, 1H), 5.25-5.05 (m, 2H), 4.80-4.70 (d, 1H), 4.50-4.35 (m, 2H), 3.82-3.75 (m, 2H), 3.55-3.45 (m, 2H), 2.35 (s, 6H), 2.15-2.05 (m, 2H).
Example 24
Preparation of Compound No. 23
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in THF (5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.7 mmol) was added and the reaction mixture stirred at RT for 10 min. 2-Chloro-N-cyclohexylacetamide (171 mg, 1.06 mmol) was added and the mixture stirred at RT for 2 h. The reaction was monitored by TLC and LCMS. On completion of reaction, the reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product obtained was purified by column chromatography to get pure product (45 mg). The pure product was converted into its oxalate salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 8 min., hold for 3 min., 90% to 10% B in 0.5 min., retention time (min.), 6.29, purity, 95.37%, flow rate, 1 mL/min.
1H NMR (CDCl3, oxalate salt) δ (ppm) 7.38 (s, 1H), 7.20 (d, 1H), 7.05 (d, 1H), 4.95 (m, 2H), 4.70 (m, 2H), 4.56 (m, 2H), 3.90 (m, 2H), 3.65 (m, 2H), 3.50 (m, 2H), 2.50 (m, 2H), 2.42 (s, 3H), 2.30 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.60 (m, 2H).
Example 25
Preparation of Compound No. 24
Sodium hydride (50%) (33 mg, 1.4 mmol) was dissolved in THF (5 mL) and stirred for 10 min. Carboline 1 (100 mg, 0.47 mmol) was added and the reaction mixture stirred at RT for 10 min. tert-Butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (148 mg, 0.56 mmol) was added and the mixture stirred at RT for 90 min. The reaction was monitored by TLC and LCMS. The reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to obtain the Boc protected product. Boc deprotection was achieved using ethanolic HCl (5 mL) at RT overnight to afford 74 mg of the title compound. The pure product was converted into oxalate salt.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 10 mM Ammonium Acetate, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 4.34, purity, 97.13%, flow rate, 1 mL/min.
1H NMR (CDCl3, oxalate salt) δ (ppm) 7.38-7.35 (s, 1H), 7.1-6.95 (m, 2H), 4.75-4.70 (m, 2H), 4.55-4.50 (d, 1H), 3.85-3.82 (d, 1H), 3.55-3.45 (m, 4H), 3.25-3.18 (m, 1H), 3.10-3.05 (m, 1H), 3.00-2.90 (m, 4H), 2.50 (s, 3H), 2.30-2.05 (m, 6H).
Example 26
Preparation of Compound No. 25
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in THF (5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.7 mmol) was added and the reaction mixture stirred at RT for 10 min. 2-Chloro-1-(4-methylpiperidin-1-yl)ethanone (186 mg, 1.06 mmol) was added and stirred at RT for 2 h. The reaction was monitored by TLC and LCMS. The reaction was quenched with ice water, and extracted with EtOAc. 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 pure product (50 mg). The pure product was converted into oxalate salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 9.14, purity, 99.19%, flow rate, 1 mL/min.
1H NMR (CDCl3, oxalate salt) δ (ppm) 7.35 (s, 1H), 7.08-7.02 (d, 1H), 6.98-6.95 (d, 1H), 4.70-4.65 (m, 2H), 4.55-4.40 (m, 2H), 3.82-3.75 (m, 2H), 3.44-3.38 (m, 2H), 3.20-2.90 (m, 3H), 2.65-2.55 (m, 2H), 2.55 (s, 3H), 2.20-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.30-1.20 (m, 1H), 1.15-1.05 (m, 2H), 0.95-0.92 (d, 3H).
Example 27
Preparation of Compound No. 26
Sodium hydride (50%) (50 mg, 2.1 mmol) was dissolved in THF (5 mL) and stirred for 10 min. Carboline 1 (150 mg, 0.7 mmol) was added and the reaction mixture stirred at RT for 10 min. 2-Chloro-1-morpholinoethanone (173 mg, 1.06 mmol) was added and stirred at RT for 2 h. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water, extracted with EtOAc. 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 pure product (70 mg). The pure product was converted into oxalate salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 5 min., 90% to 10% B in 1 min., retention time (min.), 7.42, purity, 91.26%, flow rate, 1 mL/min.
1H NMR (CDCl3, oxalate salt) δ (ppm) 7.22-7.20 (d, 1H), 7.08-7.05 (m, 2H), 4.88-4.70 (m, 2H), 4.25-4.20 (m, 1H), 3.90-3.85 (m, 2H), 3.80-3.70 (m, 4H), 3.68-3.55 (m, 4H), 3.50-3.45 (m, 2H), 3.28-3.20 (m, 2H), 2.45 (s, 3H), 2.38-2.30 (m, 2H).
Example 28
Preparation of Compound No. 27
Sodium hydride (113 mg, 4.7 mmol) was washed with hexane and dried under vacuum, and stirred in THF (5 mL). Carboline 1 (200 mg, 0.94 mmol) in THF (3 mL) was added dropwise to the reaction mixture at 0° C. The contents were stirred for 30 min. at 0° C. N,N-Dimethylchloroacetamide (148 mg, 1.2 mmol) in THF (3 mL) was added dropwise and the reaction mixture stirred at RT for 3 h. After completion of reaction, the reaction mixture was quenched with ice cold water and the product extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was washed with ether and hexane for removal of colored impurities to afford 125 mg of desired product as free base.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 6.42, purity, 94.21%, flow rate, 1 mL/min.
1H NMR (CDCl3, free base) δ (ppm) 7.35 (s, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 4.60 (s, 2H), 4.40 (d, 1H), 3.70 (d, 1H), 3.30 (m, 2H), 3.10 (m, 1H), 3.05 (s, 3H), 2.95 (s, 3H), 2.85 (m, 2H), 2.40 (s, 3H), 2.10 (m, 2H).
Example 29
Preparation of Compound No. 28
Carboline 1 (212 mg, 1 mmol) was dissolved in 2 mL NMP followed by addition of potassium hydroxide (560 mg, 10 mmol). 4-Fluoro-2-bromoacetophenone (217 mg, 1 mmol) was added to the reaction mixture, which was stirred overnight at RT. Water was added to the reaction mixture and the product extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, concentrated under reduced pressure and purified by column using silica (100-200 mesh) and 0-4% MeOH:DCM as eluent. The pure product was converted into the TFA salt.
1H NMR (CD3OD, TFA salt) δ (ppm) 8.20 (m, 2H), 7.40 (m, 3H), 7.20 (m, 1H), 7.0 (d, 1H), 5.70 (d, 1H), 5.60 (d, 1H), 5.22 (d, 1H), 5.18 (d, 1H), 4.20 (m, 2H), 4.10 (m, 1H), 3.92 (m, 2H), 2.62 (m, 1H), 2.42 (s, 3H), 2.30 (m, 1H).
Example 30
Preparation of Compound No. 29
Carboline 1 (212 mg, 1 mmol) was dissolved in 2 mL NMP followed by addition of potassium hydroxide (560 mg, 10 mmol). 2-Bromo-1-(4-chlorophenyl)-ethanone (233 mg, 1 mmol) was added to the reaction mixture, which was stirred overnight at RT. Water was added to the reaction mixture and the product extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, concentrated under reduced pressure and purified by column using silica (100-200 mesh) and 0-4% MeOH:DCM as eluent. The pure product was converted into the TFA salt.
1H NMR (CD3OD, TFA salt) δ (ppm) 8.0 (d, 2H), 7.60 (d, 2H), 7.40 (s, 1H), 7.22 (d, 1H), 7.0 (d, 1H), 5.70 (d, 1H), 5.60 (d, 1H), 5.22 (d, 1H), 5.18 (d, 1H), 4.20 (m, 2H), 4.10 (m, 1H), 3.95 (m, 2H), 2.60 (m, 1H), 2.42 (s, 3H), 2.30 (m, 1H).
Example 31
Preparation of Compound No. 30
Tetra butyl ammonium bromide (8 mg, 0.024 mmol) was dissolved in 50% aqueous sodium hydroxide (5 mL), stirred for 10 min. Carboline 1 (100 mg, 0.47 mmol) was added to it and the reaction mixture stirred for 10 min. 4-vinylpyridine (61 mg, 0.57 mmol) was added to the reaction mixture, which was stirred at 110° C. overnight. The reaction mixture was cooled to RT and extracted with EtOAc. Combined organic layers were dried over anhydrous sodium sulfate and concentrated. Crude product was purified by reverse phase chromatography to afford 50 mg of title compound as free base. The pure product was converted into TFA salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 6.75, purity, 95.52%, flow rate, 1 mL/min.
1H NMR (CDCl3, TFA salt) δ (ppm) 8.45 (d, 2H), 7.29 (s, 1H), 7.23 (s, 1H), 7.20 (d, 1H), 7.00 (d, 1H), 6.80 (d, 2H), 4.22-4.05 (m, 2H), 3.90 (d, 1H), 3.25 (d, 2H), 3.22-3.10 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.70 (m, 2H), 2.50-2.40 (m, 4H), 2.03-1.90 (m, 2H).
Example 32
Preparation of Compound No. 31
Carboline 1 (2.5 g, 11 mmol) was dissolved in dimethylformamide (25 mL) and the reaction mixture stirred for 5 min. Sodium hydride (1.3 g, 33 mmol) was added portionwise to the reaction mixture under nitrogen. 2-(4-Fluorophenyl)oxirane (2.1 g, 15 mmol) was added and stirring continued overnight at RT. After completion of the reaction, the reaction mixture was poured into ice water. The precipitate obtained was filtered, washed with water and crystallized using diethyl ether. The ether layer was concentrated under reduced pressure and the residue stirred in hexane and filtered. The pure compound was converted into oxalate salt.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 7.11, purity, 92.45%, flow rate, 1 mL/min.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.30 (m, 4H), 7.15 (m, 2H), 6.92 (m, 1H), 5.80 (m, 2H), 4.42 (m, 1H), 4.30 (m, 1H), 4.15 (m, 2H), 4.0 (m, 1H), 3.75 (m, 4H), 2.40 (s, 3H), 2.30 (m, 1H), 2.05 (m, 1H).
Example 33
Preparation of Compound No. 32
Carboline 1 (77 mg, 0.36 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.0362 mmol), L-proline (8 mg, 0.072 mmol) and potassium phosphate (154 mg, 0.724 mmol) were added, and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-chlorobenzene (100 mg, 0.434 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. 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: 17 mg.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 9.055 min., HPLC purity, 99.78%.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.48-7.46 (m, 2H), 7.40-7.36 (m, 2H), 7.26-7.10 (m 1H), 7.06-7.0 (m, 2H), 6.82 (s, 1H), 3.9-3.7 (m, 1H), 3.6-3.4 (m, 2H), 3.22-3.12 (m, 1H), 3.0-2.8 (m, 3H), 2.30 (s, 3H), 2.30-2.15 (m, 2H), 2.0 (s, 3H).
Example 34
Preparation of Compound No. 33
Carboline 1 (212 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (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. 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% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 20 mg as TFA salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1 mL/min., Retention time, 10.302 min., HPLC purity, 99.39%.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.32 (s, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 7.05 (m, 2H), 6.90 (d, 1H), 6.70 (s, 1H), 4.42 (d, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 3.65 (m, 1H), 3.56 (m, 1H), 3.30 (m, 1H), 2.90 (m, 1H), 2.42 (s, 3H), 2.38 (m, 1H), 2.30 (s, 3H), 2.20 (m, 1H).
Example 35
Preparation of Compound No. 34
Carboline 1 (212 mg, 1 mmol) was dissolved in DMF Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (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. 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% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 17 mg as TFA salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1 mL/min., Retention time, 10.826 min., HPLC purity, 95.04%.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.50-7.20 (m, 5H), 7.18 (d, 1H), 6.50 (s, 1H), 4.90 (d, 1H), 4.40 (d, 1H), 4.15 (m, 1H), 3.80 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H), 2.52 (s, 3H), 2.40 (m, 2H), 1.90 (s, 3H).
Example 36
Preparation of Compound No. 35 
Carboline 1 (212 mg, 1 mmol) was dissolved along with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-Phenanthroline (72 mg, 0.4 mmol) and potassium phosphate (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 mL) and flushed with nitrogen. The reaction mixture was heated at 80° C. overnight (16 h). Product was detected by LCMS. The reaction mixture was filtered through Celite, washed with DCM, and dried over sodium sulfate. The combined organic phase was concentrated under reduced pressure and without workup, purified by column chromatography (Silica gel-60-80% EtOAc in hexane) to get (23 mg) of product as a brown semi-solid.
Analytical HPLC: Sunfire C18, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 8.42, purity, 93.30%, flow rate, 1 mL/min.
1H NMR (CDCl3, free base) δ (ppm) 7.40 (m, 2H), 7.38 (d, 2H), 7.22 (m, 2H), 7.05 (d, 1H), 4.50 (d, 1H), 3.90 (d, 1H), 3.38 (m, 2H), 3.10 (m, 1H), 2.90 (m, 2H), 2.42 (s, 3H), 2.10 (m, 2H).
Example 37
Preparation of Compound No. 36
Alkyne Compound No. 35 was stirred in acetonitrile (0.5 mL) and water (0.5 mL). TFA (5-6 drops) was added. The reaction mixture was heated at 55° C. for 1 h. The solvent was then evaporated under reduced pressure, and the residue was purified by reverse phase HPLC.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 9.75, purity, 98.72%, flow rate, 1 mL/min.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.64 (d, 1H), 7.36 (m, 3H), 7.20 (m, 3H), 5.15 (d, 1H), 4.65 (d, 1H), 4.35 (s, 2H), 4.10 (m, 1H), 3.70 (m, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 3.20 (m, 1H), 2.50 (s, 3H), 2.35 (m, 2H).
Example 38
Preparation of Compound No. 37
Carboline 1 (212.29 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (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-fluorobenzene (260 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 14 mg as TFA salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1 mL/min., Retention time, 10.016 min., HPLC purity, 99.46%.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.20 (m, 3H), 7.10 (d, 1H), 6.90 (m, 3H), 6.72 (s, 1H), 4.22 (d, 1H), 3.95 (d, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 3.22 (m, 1H), 2.70 (m, 1H), 2.42 (s, 3H), 2.35 (m, 1H), 2.30 (s, 3H), 2.20 (m, 1H).
Example 39
Preparation of Compound No. 38
Carboline 1 (212.29 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (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-fluorobenzene (260 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 20 mg as TFA salt.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1 mL/min., Retention time, 10.462 min., HPLC purity, 95.23%.
1H NMR (CDCl3, TFA salt) δ (ppm) 7.40 (m, 3H), 7.20 (m, 4H), 6.70 (s, 1H), 4.90 (d, 1H), 4.40 (d, 1H), 4.10 (m, 1H), 3.82 (m, 1H), 3.70 (m, 1H), 3.60 (d, 1H), 3.30 (m, 1H), 2.46 (s, 3H), 2.42 (m, 2H), 2.0 (s, 3H).
Example 40
Preparation of Compound No. 39
Carboline 1 (76 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 potassium phosphate (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. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 43 mg.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 10.478 min., HPLC purity, 98.90%.
1H NMR (CD3OD, oxalate salt) δ (ppm) 7.58 (m, 1H), 7.42 (m, 2H), 7.35 (m, 1H), 7.10 (m, 2H), 6.98 (s, 1H), 4.42 (d, 1H), 3.95 (m, 3H), 3.70 (m, 2H), 3.45 (m, 1H), 2.50 (m, 1H), 2.42 (s, 3H), 2.30 (m, 1H), 1.95 (s, 3H).
Example 41
Preparation of Compound No. 40
Carboline 1 (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 potassium phosphate (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. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 48 mg.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 11.241 min., HPLC purity, 96.35%.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.90 (s, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 4.75 (m, 1H), 4.42 (m, 1H), 3.80 (m, 2H), 3.20 (m, 3H), 2.40 (s, 3H), 2.30 (m, 1H), 2.10 (m, 1H), 1.90 (s, 3H).
Example 42
Preparation of Compound No. 41
Carboline 1 (72 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 potassium phosphate (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. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 17 mg.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 10.369 min., HPLC purity, 84.98%.
1H NMR (CD3OD, oxalate salt) δ (ppm) 7.40 (m, 3H), 7.18 (t, 1H), 7.10 (d, 2H), 6.92 (s, 1H), 4.50 (m, 1H), 3.95 (s, 3H), 3.82 (m, 2H), 3.70 (m, 2H), 3.50 (m, 2H), 2.42 (s, 3H), 2.30 (m, 2H), 1.90 (s, 3H).
Example 43
Preparation of Compound No. 42
Carboline 1 (200 mg, 0.943 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (17 mg, 0.089 mmol), L-proline (21 mg, 0.18 mmol) and potassium phosphate (401 mg, 1.88 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (224 mg, 1.13 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 90° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 80 mg.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 7.223 min., HPLC purity, 98.63%.
1H NMR (CD3OD, TFA salt) δ (ppm) 8.95 (s, 1H), 8.70 (s, 1H), 8.42 (d, 1H), 7.80 (m, 1H), 7.42 (s, 1H), 7.22 (s, 1H), 7.10 (m, 2H), 4.95 (m, 1H), 4.55 (d, 1H), 3.90 (m, 2H), 3.70 (m, 1H), 3.62 (m, 1H), 3.50 (m, 1H), 2.50 (m, 1H), 2.42 (s, 3H), 2.36 (m, 1H), 2.05 (s, 3H).
Example 44
Preparation of Compound No. 43
Carboline 1 (212 mg, 1 mmol) was mixed with copper sulfate (50 mg, 0.2 mmol), 1,10-Phenanthroline (72 mg, 0.4 mmol), potassium phosphate (425 mg, 2 mmol) and 1-(bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) in toluene (8-10 mL), and the suspension was purged with nitrogen. The reaction mixture was at 80° C. overnight (16 h). The reaction mixture was cooled to RT, filtered through Celite, and the Celite bed washed with DCM. The combined organic layer was concentrated and the residue purified by silica gel chromatography (60-80% EtOAc in hexane) to obtain (23 mg) of a brown semi solid. This solid was stirred in acetonitrile and water (1:1) and TFA (5-6 drops) was added. The solution was stirred at 55° C. for 1 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, mobile phase A: 0.05% TFA, mobile phase B: Acetonitrile, gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., retention time (min.), 9.46, purity, 99.27%, flow rate, 1 mL/min.
1H NMR (CD3OD, TFA salt) δ (ppm) 7.82 (d, 1H), 7.50 (s, 1H), 7.35 (m, 2H), 7.25 (d, 1H), 7.08 (t, 2H), 4.50 (s, 2H), 3.90 (m, 2H), 3.65 (m, 1H), 3.60 (s, 3H), 3.50 (m, 1H), 2.42 (s, 3H), 2.30 (m, 2H).
Example 45
Preparation of Compound No. 44
Carboline 1 (106 mg, 0.5 mmol) and potassium phosphate (212 mg, 1 mmol) were dissolved in DMF and the suspension was purged with nitrogen. The suspension was heated at 90° C. for 5 min. In a separate round bottomed flask, 4-(1-bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol) and copper (I) iodide (9.5 mg, 0.05 mmol) were dissolved in DMF, the suspension was purged with nitrogen, and heated at 90° C. for 5 min. at which point it became a clear solution. The contents in the two reaction flasks were mixed and the reaction mixture was heated at 90° C. overnight. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by silica gel chromatography (100-200 mesh, neutralized with aqueous ammonia) eluting with 0-2% MeOH-DCM as eluant. The product was further purified by reverse phase HPLC.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 7.109 min., HPLC purity, 99.05%.
1H NMR (CD3OD, TFA salt) δ (ppm) 8.78 (d, 2H), 8.10 (d, 2H), 7.60 (s, 1H), 7.45 (d, 1H), 7.10 (s, 2H), 4.95 (d, 1H), 4.55 (d, 1H), 3.95 (m, 2H), 3.70 (m, 2H), 3.50 (m, 1H), 2.55 (m, 1H), 2.45 (s, 3H), 2.36 (m, 1H), 2.10 (s, 3H).
Example 46
Preparation of Compound No. 45
Carboline 1 (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 potassium phosphate (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. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 18 mg.
Analytical HPLC: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile PhaseA: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min., hold for 10 min., 90% to 10% B in 1 min., Flow Rate, 1.0 mL/min., Retention time, 10.409 min., HPLC purity, 83.30%.
1H NMR (DMSO, oxalate salt) δ (ppm) 7.50 (d, 2H), 7.42 (s, 1H), 7.10 (d, 1H), 6.98 (m, 4H), 4.80 (m, 1H), 4.42 (m, 1H), 3.80 (s, 3H), 3.70-3.50 (m, 4H), 2.40 (s, 3H), 2.18 (m, 2H), 1.90 (s, 3H), 1.75 (m, 1H).
Example 47
Preparation of Compound No. 71
To a solution of 7-methyl-3,4,5,10-tetrahydro-1H-2,5-methanoazepino[3,4-b]indole (1.0 g, 4.7 mmol) in DMF was added sodium hydride (564 mg, 14.1 mmol). After stiffing at RT under nitrogen for 5 min, a solution of 4-oxiranylpyridine (856 mg, 7.0 mmol) in DMF (5 mL) was added into the reaction mixture and stirring continued at RT. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice water and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (5×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized in ether-hexane to yield the desired compound (1.0 g).
1H NMR (CDCl3, free base) δ (ppm) 8.58 (t, 2H), 7.32 (s, 1H), 7.2 (t, 2H), 7.18 (d, 1H), 6.9 (d, 1H), 5.0 (m, 1H), 4.23 (d, 1H), 4.02 (m, 2H), 3.62 (d, 1H), 3.1-3.3 (m, 3H), 2.8 (m, 2H), 2.7 (m, 1H), 2.42 (s, 3H), 2.0 (m, 3H).
Example 48
Preparation of Compound No. 72
To a solution of 1-ethyl-7-methyl-3,4,5,10-tetrahydro-1H-2,5-methanoazepino[3,4-b]indole (1000 mg, 4.17 mmol) in DMF (10 mL) was added sodium hydride (500 mg, 12.498 mmol) portionwise. After stirring at RT for 5 min, 4-(oxiran-2-yl)pyridine (630 mg, 5.00 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. The reaction mixture was quenched with ice-water and the solid mass was filtered. The residue was washed with water (2×10 mL), hexane (2×50 mL) and purified by reverse phase HPLC to yield the title compound.
Example 49
Preparation of Compound No. 73
To a solution of 1,7-dimethyl-3,4,5,10-tetrahydro-1H-2,5-methanoazepino[3,4-b]indole (1 g, 4.42 mmol) in DMF (10 mL) was added sodium hydride (530 mg, 13.24 mmol) portionwise under nitrogen. After stirring for 10 min at 0° C., 4-oxiranyl-pyridine (1.07 g, 8.84 mmol) was added dropwise at 0° C. into the reaction mixture and stirring continued for 12 h at RT. After completion, the reaction mixture was poured into ice water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (5×50 mL), dried over sodium sulfate and concentrated to obtain 1.2 g of product.
1H NMR (CD3OD, Formate salt) δ (ppm) 8.42 (d, 2H), 7.8 (d, 2H), 7.22 (s, 1H), 6.78 (t, 2H), 5.67 (q, 1H), 5.4 (m, 1H), 4.77 (dd, 1H), 4.4 (dd, 1H), 3.82 (d, 1H), 3.7-3.8 (m, 3H), 3.6 (d, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 2.18 (m, 1H), 1.97 (d, 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. (1993), 197(3):1601] 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 2.
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. (1990), 87(5):1658] 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 2.
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. (1994), 65(2):107; Zhu Y et al., Mol Pharmacol. (2001), 59(3): 434] 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. (1990), 99:803] 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 then 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 2







Binding data


(Percentage Inhibition)









Histamine 


Compound
Binding (1 μM)









No.
H1
H2












1
32
0


2
21
8


3
59, 60
25


4
67
5


5
48
4


6
86
−5


7
17
−4


8
33
2


9
89
6


10
70
6


11
77
−2


12
59
4


13
24
8


14
37
24


15
82
13


16
20
10


17
16
4


18
21
16


19
82
−9


20
21
2


21
40
−6


22
52, 58
15


23
13
−3


24
 5
−3


25
30
−4


26
17
−1


27
10
−3


28
64
18


29
56
19


30
76
18


31
42
5


32
85
82


33
76
35


34
34
40


35
 0
19


36
45
20


37
78
22


38
38
7


39
26
20


40
57
39


41
21
24


42
20
1


43
16
7


44
23
−3


45
26
21









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. (1989), 98:883] in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 0.25 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 of the invention were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1992), 186:760; Michel, A. D. et al., Br. J. Pharmacol. (1989), 98:883] in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 0.25 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. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1995), 115(6):981] 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. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1994), 271:1558] 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 was (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-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. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1998), 343(1):93] 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. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1994), 271:1558] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 2 mM EDTA) was used. Compounds of the invention were incubated with 1 nM [3H]MK-912 for 60 min. at 25° C. Non-specific binding was estimated in the presence of 10 μM WB-4101. 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. Compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds were presented as the percent inhibition of specific binding in Table 3.
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. (1989), 86:9762; Hayes, G. et al., Mol. Endocrinol. (1992), 6:920] 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 3.







TABLE 3





Percent Inhibition of ligand 


binding to aminergic G protein-coupled


receptors by compounds of the invention:




















Adrenergic 
Dopamine 



Compound
(1 μM ligand conc.)
(1 μM ligand conc.)













No.
α1D
α2A
α2B
D2L







1
51
25
7
8



2
15
54
84
7



3
93
93
93
12, 21



4
54
54
89
3



5
34
44
78
6



6
28
23
73
−1



7
−7
9
0
−3



8
20
1
34
−16



9
24
2
45
9



10
73
38
66
18



11
26
−15
48
−6



12
25
−4
16
0



13
14
39
99
−2



14
−5
18
68
11



15
28
21
106
0



16
24
28
103
5



17
19
4
90
5



18
1
30
107
−1



19
34
−10
61
−2



20
29
28
97
9



21
−4
5
20
−2



22
81
93
95
21, 25



23
18
−13
−6
5



24
2
4
−4
−8



25
−1
−7
−17
9



26
6
−4
7
10



27
9
5
−15
11



28
49
86
45
1



29
42
89
58
0



30
40
84
76
10



31
34
41
79
2



32
80
96
98
−12



33
28
66
73
−6



34
11
48
55
0



35



−6



36



3



37



5



38



1



39



0



40



6



41



17



42



−10



43



11



44



9



45



−2














Compound 
Adrenergic (0.1 μM ligand conc.)















No.
α1A
α1B
α1D
α2A
α2B
α2C







32
36
67
9
45
56
39



33
3
28
−6
13
9
16



36
−18
4
−2
24
13
24



38
14
29
−3
3
25
13



44
−7
4
8
−5
9
7



45
24
20
−1
4
15
3










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 et al. Neuropharmacol. (1994), 33:261; May J A et al. J. Pharmacol. Exp. Ther. (2003), 306(1):301] 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. (1985), 118:1; Pazos et al., Eur. J. Pharmacol. (1985), 106:531] 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. (1995), 115:622; Saucier, C. et al., J. Neurochem. (1997), 68:1998] 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 4.
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. (1995), 115:622] 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. Biochemical assay results may be presented as the percent inhibition of specific binding.
Serotonin (5-Hydroxytryptamine) 5-HT2 
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. et al., J. Neurochem. (1997), 69:1449] 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 4.
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. (1992), 11:58; Boess, F., et al., Neuropharmacology. (1997), 36:637] 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. (1993), 109:618] 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. (1994), 355:242] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 1.7 nM [3H]Lysergic acid diethylamide (LSD) for 60 min. at 37° C. Non-specific binding was estimated in the presence of 100 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. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 4.
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. (1993), 43:320] 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 4.
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. (1994), 268:1403; Shen, Y. et al., J. Biol. Chem. (1993), 268:18200] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 0.5 mM EDTA) was used. Compounds of invention were incubated with 5.5 nM [3H] Lysergic acid diethylamide (LSD) for 2 h at 25° C. Non-specific binding was estimated in the presence of 10 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 4.







TABLE 4







Percent Inhibition of ligand 


binding to aminergic G protein-coupled 


receptors by compounds of the invention:










Compound
Serotonin (1 μM ligand concentration)













No.
5-HT2A
5-HT2C
5-HT6
5-HT7

















1
18
10
10




2
76
57
58




3
94
97
105




4
49
31
56




5
81
53
14




6
45
43
22




7
−3
2
0




8
25
12
11




9
−6
4
40




10
20
9
−4




11
10
17
20




12
17
5
2




13
82
83
17




14
61
87
1




15
82
87
59




16
92
92
29




17
81
92
9




18
81
87
49




19
0
23
9




20
102
94
13




21
16
−4
29




22
97
96
102




23
−4
11
4




24
3
5
5




25
2
15
−2




26
5
20
4




27
−4
−1
5




28
61
83
15
82



29
56
74
32
81



30
71
85
33
95



31
58
46
46
73



32
86
92
97
96



33
78
95
35
96



34
94
99
21
86



35
87
94
12
35



36
89
89
38
75



37
96
94
70
93



38
90
93
58
95



39
94
94
81
96



40
94
89
12
95



41
92
97
48
90



42
47
64
26
92



43
48
66
7
41



44
67
58
97
80



45
98
98
80
93










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. et al., Eur. J. Pharmacol. (2001), 414:23-30] 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., J. Neurochem. (1996), 66:47] 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 D21 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. (1990), 265(8):4507] 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 minute incubation period. Increase of [35S]GTPγS binding by 50% or more (350%) relative to the 1 mM dopamine response by compounds of the invention indicates possible dopamine D2L receptor agonist activity. Inhibition of a 10 μM dopamine-induced increase of [35S]GTPγS binding response by 50% or more (350%) by compounds of the invention 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 et al. Naunyn-Schmiedeberg's Archives of Pharmacology. (2000), 361:498] 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 minute incubation period. Increase of [35S]GTPγS binding by 50 percent or more (350%) relative to the 100 μM dopamine response by compounds of the invention indicates possible dopamine D2S receptor agonist activity. Inhibition of a 3 μM dopamine-induced increase of [35S]GTPγS binding response by 50% or more (350%) by compounds of the invention 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 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. et al. J. Biomol. Screen. (1999), 4:249-258] 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
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 attach 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 0.01M 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. et al., Behav. Brain Res. (1988), 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 [Scali, C. et al., Neurosci. Letts. (1994), 170:117-120; Bartolini, L. et al., Biochem. Behav. (1996), 53:277-283].
Male Sprague-Dawley rats between six and seven weeks old, weighing between 220-300 grams are obtained, e.g., 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 h light/12 h 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 3 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 sec. of object exploration is determined, with a cut-off time of 4 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 is 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 sec. 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 (ΔTNovel−TFamiliar) is evaluated. The % of animals in each group with TNovel−TFamiliar greater than or equal to 5 sec. 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. Thus, only rats exploring the objects for at least five sec. (TNovel+TFamiliar>5 sec.) 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 forty 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 percent of good learners for compounds 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 [Jentsch et al., Science (1997), 277:953-955; Piercey et al., Life Sci. (1988), 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., C57B1/6J) 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 remain housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for at least 2 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% Tween80 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., C57B1/6J) 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 2 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 plexiglass 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 days/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. The ability of compounds of the invention to bind receptors detailed hereinabove is evaluated in multiple concentrations.
Example B16
Use of the 5-Choice Serial Reaction Task to Determine the Ability of Compounds to Enhance Attention/Vigilance and Reduce Impassivity
Attention and impulsivity are characteristic of several disease states. The continuous performance test (CPT), used in humans, is capable of detecting attention deficits in a number of disorders, including attention deficit hyperactivity disorder [Riccio et al., J. Neuropsychiatry Clin. Neurosci. (2001), 13(3):326-335], schizophrenia [Lee, et al., Schizophr. Res. (2006), 81(2-3):191-197] and mild cognitive impairment [Levinoff et al., Neuropsychology (2006), 20(1):123-132]. The pre-clinical analogue of the CPT is the 5-choice serial reaction time task [“5-CSRTT”; Robbins, T., Psychopharmacology (2002), 3-4:362-380]. In this operant-based test, rats are required to be attentive and withhold responding while they monitor 5 apertures for the appearance of a brief stimulus light in one of the apertures. The brief illumination of the stimulus light in the 5-CSRTT is analogous to the appearance of the “correct” letters in the CPT in humans. Upon observing the stimulus light, the rat must nose-poke in the corresponding aperture to receive a food reward. The 5-CSRTT allows the measurement of similar behavioral responses as the CPT, including accuracy, speed of responding, impulsive and compulsive responding. In the present studies, drug tests are performed under altered test parameters which results in increased premature responding. This premature responding is hypothesized to indicate impulsivity, i.e., a failure to withhold an inappropriate response, and has been shown to be sensitive to atomoxetine [Navarra, et al. Prog. Neuropsychopharmacol. Biol. Psychiatry (2008), 32(1):34-41].
A minimum of 12 male Long-Evans rats (275-300 g) are obtained from Harlan Laboratories, Indianapolis, Ind. At the time of testing, rats are approximately 16-18 months old. Upon arrival, the rats are assigned unique identification numbers (tail marked). Rats are single-housed in OptiRAT cages and acclimated for 7 days prior to commencing a food-restriction regimen: rats are held at 85% of age-matched free-feeding control body-weights, receiving approximately 10-20 g of rat chow daily. Water is provided ad libitum, except during testing. Animals are maintained in a 12/12 h light/dark cycle (lights on at 0700 EST) with RT maintained at 22±2° C. and the relative humidity maintained at approximately 50%. All animals are examined, handled and weighed prior to initiation of the study to assure adequate health and suitability and to minimize non-specific stress associated with testing. The 5-CSRTT sessions are performed during the animal's light cycle phase. All experiments and procedures are approved by the Institutional Animal Care and Use Committee of PsychoGenics, Inc.
Apparatus: The apparatus consists of aluminum and Plexiglas chambers with grid floors (width 31.5 cm, depth 25.0 cm, height 33.0 cm), housed in sound-attenuating cabinets. Each cabinet is fitted with a low-level noise extractor fan which also helps to mask external noise. The left wall of each chamber is concavely curved with 5 apertures evenly spaced, located approximately 2.5 cm from the floor. Each aperture contains a standard 3W LED to serve as stimulus lights. The opposite wall contains a food magazine, located approximately 3.0 cm from the floor. Each chamber is illuminated with a 3W house-light located in the center of the ceiling panel. After each test session the apparatus is cleaned with 70% ethanol.
Experimental procedure: Training: Animals are trained to monitor the five apertures for stimulus light illumination. Each session is initiated by the illumination of the house light, and the delivery of a food reward into the magazine. The first trial begins when the rat opens the magazine to obtain the food pellet. After the inter-trial interval (ITI) one of the stimulus lights is illuminated for 500 msec. The rat must nose-poke in the illuminated aperture either during or within 5 sec. of stimulus light illumination. Such a response is defined as a correct response, and is rewarded with delivery of a food pellet. Collection of the pellet initiates the next trial. A nose-poke response in a non-illuminated aperture (incorrect response) or a nose-poke after the 5 sec. limited hold (missed trial) results in termination of the trial with extinction of the house-light and imposition of a time-out period. Testing: After acquisition of the 5-CSRTT with a high level of accuracy (at least 75% correct, at least 50 trials completed per session), drug testing begins. Animals are treated with test compound (various doses, appropriate vehicle), vehicle and positive control (atomoxetine 1 mg/kg ip). During drug test sessions, the ITI is varied between 10, 7, 5 or 4 sec. in duration, presented in groups of 4 trials (each of which contains 1 trial at each ITI duration in a randomized order). The session ends when 60 min. have elapsed. All rats receive all drug treatments, according to a randomized-order within-subjects design. Drug tests are performed on Wednesdays and Fridays of each week, only when rats have performed at least 75% correct trials for a minimum of 50 trials in the previous test session.
Measures obtained during the test sessions are: (1) percent correct, defined as the number of correct trials X 100, divided by the total number of correct and incorrect trials, (2) missed trials, defined as responding beyond the 5 sec. limited hold or failing to respond, (3) correct latency, defined as the time taken to make a correct response after the illumination of the stimulus, (4) magazine latency, defined as the time taken to enter the magazine to collect the food pellet after making a correct response, (5) premature responding, defined as the total number of nose-poke responses made during the ITI, and (6) perseverative responding, defined as the total number of additional responses emitted after the initial nose-poke.
Statistical Analysis
Data are expressed as percent correct; the numbers of missed trials, preliminary and perseverative responses; and latencies (in sec.) to make correct responses and to collect food pellets after a correct response. Data are analyzed by analyses of variance (ANOVA). In all cases, values of p<0.05 are considered to be significant. Post-hoc comparisons are made using Fisher LSD post-hoc tests where appropriate.
Example B17
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 B18
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 B19
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 C57B1/6J mice.
Male C57B1/6J 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×35 1 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 method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound of formula (I):




or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2 moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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-C8alkenyl, substituted or unsubstituted C2-C8 alkenyl, 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;
m and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl; and
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
and provided that:
(A) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety, provisions (a)-(d) apply: (a) when each X7, X8 and X10 is CH, X9 is CR4 where R4 is H or methoxy, each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, (b) when each X7-X10 is CH, each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is other than dimethylamino, (c) when each X7-X10 is CH, q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than pyrrolidin-1-yl, and (d) when each X7-X10 is CH, each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(B) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and each X7-X10 is CR4 where R4 is H, provisions (f)-(k) apply: (f) when each q, m and n is 1 and each R8a, R8b, R8c, R8d, R8e and R8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R8a, R8b, R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R8c and R8d is H and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R8e and R8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl], and (k) when each q and m is 0, n is 1 and R8e and R8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;
(C) when R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety and each X7-X10 is CH, R8(a-f), m, n, q and Q are not taken together to form a tert-butoxycarbonyl group;
(D) when R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b and R10b are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;
(E) when R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, X7-X10 is CR4, each R2a, R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;
(F) when R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, X7-X10 is CR4, each R2b, R3b, R10a and R10b are H, then (i) at least one of R8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl; and
(G) when R1 and R3a are taken together to form a butylene (—CH2CH2CH2CH2—) moiety and when q is 0, each m and n is 1 and each R8c, R8d, R8e and R8f is H, Q is other than cyano.

2. The method of claim 1, wherein in the compound or a pharmaceutically acceptable salt thereof, q is 0 and m is 1.

3. The method of claim 2, wherein in the compound or a pharmaceutically acceptable salt thereof, X7, X8 and X10 are CR4 where R4 is H.

4. The method of claim 1, wherein in the compound or a pharmaceutically acceptable salt thereof, X8 and X10 are CR4 where R4 is H; X9 is CR4; q is 0; m is 1 and R8c and R8d are both H.

5. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (II):




or a pharmaceutically acceptable salt thereof, wherein:
R2b is H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R3a and R3b is independently H, halo, or substituted or unsubstituted C1-C8 alkyl;
each R10a and R10b is independently H, halo, or a substituted or unsubstituted C1-C8 alkyl;
p is 1 or 2;
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 alkenyl, 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;
m and q are independently 0 or 1;
n is 1;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-f) 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(a-f) to form a bond provided when an R8(a-f) is taken together with a vicinal R8(a-f) to form a bond, the geminal R8(a-f) is other than hydroxyl; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino.

6. The method of claim 5, wherein the compound or a pharmaceutically acceptable salt thereof, each X7, X8, X9 and X10 is independently CR4.

7. The method of claim 5, wherein in the compound or a pharmaceutically acceptable salt thereof, p is 1; q is 0 and m is 1.

8. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (III):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

9. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (IV):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

10. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (V):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

11. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (VI):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

12. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (VII):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

13. A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound of the formula (A):




or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy cyano, nitro, or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R10a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R10a and R1a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) 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;
m and q are independently 0 or 1, provided that at least one of m and q is 0;
each R8a, R8b, R8c and R8d is independently H, hydroxyl, halo, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C8alkenyl, C1-C8perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R11 and R12 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, carboxy, carbonylalkoxy or C1-C8 perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R11 and R12 are taken together to form a bond or 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; and
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(vi): (i) R1 and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; (ii) R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iii) R1 and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; (iv) R2a and R3a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; (v) R2a and R10a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; and (vi) R3a and R10a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety.

14. The method of claim 13, wherein the compound, or a pharmaceutically acceptable salt thereof, is a compound of the formula (B):




or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

15. The method of claim 1, wherein the compound is selected from compounds 1-7 in Table 1, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1, wherein the compound is selected from compounds 8-73 in Table 1, or a pharmaceutically acceptable salt thereof.

17. The method of claim 1, wherein the cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or neuronal disorder is schizophrenia.

18. The method of claim 13, wherein the cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or neuronal disorder is schizophrenia.