HK1176813B

HK1176813B - Pyrido[3,4-b]indoles and methods of use

Info

Publication number: HK1176813B
Application number: HK13104014.9A
Authority: HK
Inventors: Rajendra Parasmal Jain; Sarvajit Chakravarty
Original assignee: Medivation Technologies, Inc.
Priority date: 2009-09-23
Filing date: 2010-09-23
Publication date: 2015-12-11

Description

Pyrido [3,4-b ] indole compounds and methods of use thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority of the present application claims U.S. provisional patent application 61/245,147 filed on 9/23/2009 and U.S. provisional patent application 61/245,260 filed on 9/23/2009, the respective disclosures of which are incorporated herein by reference in their entireties.

Statement of rights to invention made in federally sponsored research project

Not applicable.

Background

Neurotransmitters such as histamine, serotonin, dopamine and norepinephrine mediate a number of physiological processes within and outside the Central Nervous System (CNS). Abnormal neurotransmitter levels are associated with a variety of diseases and conditions including, but not limited to, alzheimer's disease, parkinson's disease, autism, gillander's syndrome, mild cognitive impairment, schizophrenia (e.g., cognitive impairment associated with schizophrenia (CIAS), positive symptoms, deconstruction disorders (dissonazid s) and negative symptoms of schizophrenia), anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorder, psychosis, depression, ATTENTION deficit and hyperactivity disorder (ATTENTION-DEFICITHYPERACTIVITY DISORDER) (ADHD), depression, and a variety of allergic disorders. Compounds that modulate these neurotransmitters may be useful therapeutic agents.

The histamine receptor belongs 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. The coding sequences for these receptors in those regions believed to be involved in the agonist-antagonist binding site are highly conserved in mammalian species. Histamine receptors are found in most peripheral tissues and in the central nervous system. Compounds that modulate histamine receptors are useful in therapy, for example as antihistamines.

Dimebon is a known antihistamine and has also been identified as a neuroprotective agent useful in the treatment of inter alia neurodegenerative diseases. Dimebon has been shown to inhibit brain cell (neuronal) death in preclinical models of alzheimer's disease and huntington's disease, making it a new potential treatment for these and other neurodegenerative diseases. In addition, Dimebon was shown to be highly effective in improving mitochondrial function in cells under cell stress. For example, treatment with Dimebon can improve mitochondrial function and increase the number of surviving cells in a dose-dependent manner following treatment with the cytotoxic ionomycin. Dimebon has also been shown to promote neuronal synaptic growth and neurogenesis, processes important in the formation of new and/or enhanced neuronal cell connections, and also provides evidence that Dimebon has potential for use in additional diseases or disorders. See, e.g., U.S. patents 6,187,785 and 7,071,206 and PCT patent applications 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/US 2008/008121. Hydrogenated pyrido [4, 3-b ] indole compounds and uses thereof are also disclosed in PCT patent applications PCT/US2008/081390, PCT/US2009/032065 and PCT/US 2009/038142. Hydrogenated pyrido [3, 4-b ] indole compounds and their use are also disclosed in PCT/US 2009/038138. All references, such as publications, patents, patent applications, and published patent applications, disclosed herein are incorporated by reference in their entirety.

Although Dimebon holds great promise as a drug for the treatment of neurodegenerative diseases and/or diseases in which neuronal synaptic growth and/or neurogenesis may be implicated in therapy, there remains a need for new alternative therapeutic agents for the treatment of such diseases or conditions. Furthermore, there remains a need for new alternative antihistamines, preferably antihistamines that do not have or have reduced side effects (such as lethargy). Compounds that exhibit enhanced and/or more desirable properties (e.g., better safety and efficacy) as compared to Dimebon are particularly useful for treating indications for which at least Dimebon is believed to be beneficial. Moreover, compounds that exhibit therapeutic properties other than Dimebon, as determined by, for example, in vitro and/or in vivo assays, may be useful for additional diseases and conditions.

Disclosure of Invention

The invention provides hydrogenated pyrido [3, 4-b ] indole compounds, compositions and kits containing the compounds, methods of using the compounds and processes for preparing the compounds. The compounds provided by the invention can be used for treating neurodegenerative diseases. The compounds of the invention may also be useful in the treatment of diseases and/or conditions in which modulation of aminergic G protein-coupled receptors and/or neuronal synaptic growth is therapeutically relevant. The compounds disclosed herein may be used in the methods disclosed herein, including in an individual in need of such treatment for treating, preventing, delaying the onset and/or delaying the progression of cognitive, psychiatric, neurotransmitter-mediated diseases and/or neuronal diseases.

In one aspect, the present invention provides a compound of formula (I):

wherein:

R¹is H, hydroxy, nitro, cyano, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, mercapto, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^2aAnd R^2bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, cyano, hydroxy, alkoxy, nitro, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R ^2aAnd R¹Together forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R^2aAnd R^3aTogether form methyleneRadical (-CH)₂-) or ethylene (-CH)₂CH₂-, or R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^3aAnd R^3bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, cyano, nitro, hydroxy, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy, or R^3aAnd R^3bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R^3aAnd R¹Together form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^3aAnd R^2aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-, or R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

Each R^10aAnd R^10bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, hydroxy, alkoxy, cyano, nitro, or R^10aAnd R^10bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R^10aAnd R¹Together form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^2aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^3aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

Each X ⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

Each R⁴Independently H, hydroxy, nitro, cyano, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxy, carboxyl, carbonylalkoxy, mercapto, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, sulfanyl, 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 R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene group or a group of the formula-OCH ₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclesRadicals, or R in vicinal position^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, or acylamino;

provided that the compound satisfies one of the following conditions (i) to (vi): (i) r¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；(ii)R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iii)R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iv)R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)；(v)R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH) ₂CH₂CH₂CH₂-) according to the formula (I); and (vi) R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

And the premise is that:

(A) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-, the following conditions (a) to (d) apply: (a) when each X is⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H), X⁹Is CR⁴(wherein R is⁴Is H or methoxy), each q and m is 0, n is 1 and each R^8eAnd R^8fWhen H, Q is not phenyl, (B) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each q, m and n is 1 and each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not dimethylamino, (c) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not pyrrolidin-1-yl, and (d) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each of q and m is 0, n is 1 and R^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group;

(B) when R is¹And R^3aTogether form butylene (-CH)₂CH₂CH₂CH₂-) and each X⁷-X¹⁰Is CR⁴(wherein R is⁴In the case of H), the conditions (f) to (k) apply: (f) when each of q, m and n is 1 and each R is^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen it is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl which is not substituted azetidinyl, alkoxy, carbonylalkoxy or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R ^8a、R^8b、R^8cAnd R^8dIs H and R^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not a substituted amino group of the formula-NHR, wherein R is substituted alkyl, (h) when Q is 0, each of m and n is 1 and R is^8c、R^8d、R^8eAnd R^8fWhen H, Q is not carboxy and an acylamino group of the formula-C (O) NHR, wherein R is substituted alkyl, (i) Q is 0, eachm and n are 1, each R^8cAnd R^8dIs H and R^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not methoxy and cyclopentylamino, (j) when each Q and m is 0, n is 1 and each R is^8eAnd R^8fWhen H, Q is not phenylamino [ -C (O) NH-cyclopentyl substituted by phenyl, methoxy, carboxyl, carbonylmethoxy and cyclopentyl]And (k) when each of q and m is 0, n is 1 and R is^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group;

(C) when R is¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) and each X⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), R^8(a-f)M, n, Q and Q do not together form a tert-butoxycarbonyl group.

In another variation, the compound of formula (I) is as described above, provided that the above conditions (a) - (C) and/or one or more (in one variation, all) of conditions (D), (E), (F) and (G) apply:

(D) when R is^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH) ₂CH₂CH₂-, each X⁷-X¹⁰Is CR⁴And each R^2a、R^2b、R^3bAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl;

(E) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, each X⁷-X¹⁰Is CR⁴And each R^2a、R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl;

(F) when R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)，X⁷-X¹⁰Is CR⁴And each R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl; and

(G) when R is¹And R^3aTogether form butylene (-CH)₂CH₂CH₂CH₂-) and when q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen it is H, Q is not cyano,

or a pharmaceutically acceptable salt thereof.

In one variant of formula (I), the conditions (A) to (C), (D), (F) and (G) apply. In one variation, when the compound is a compound of formula (I), conditions (D), (E), and (F) are applicable. In one variation, when the compound is a compound of formula (I), conditions (A), (B), (C), (D), (E), (F), and (G) are applied.

In one variation, the compound of formula (I) has one or more of the following structural features: (1) x ⁷、X⁸、X⁹And X¹⁰At least one of which is N; (2) r present⁸At least one of the radicals is other than H (e.g., when q, m and n are all 1, at least one R^8a-R^8fNot H, e.g. at least one R⁸The group is alkyl, alkoxy or hydroxy); (3) q is not substituted heteroaryl; and (4) R¹Is substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or acyl.

In another aspect, the present invention provides a compound of formula (a):

wherein:

R¹is H, hydroxy, nitro, cyano, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, mercapto, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH) ₂CH₂CH₂-, or R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^2aAnd R^2bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, cyano, hydroxy, alkoxy, nitro, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R^2aAnd R¹Together forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-, or R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^10aAnd R^10bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, hydroxy, alkoxy, cyano, nitro, or R ^10aAnd R^10bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R^10aAnd R¹Together form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^2aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^3aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

Each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

each R^8a、R^8b、R^8cAnd R^8dIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C ₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-d)Together form a substituted or unsubstituted methylene group or a group of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-d)And the carbons to which they are attached together form a carbonyl or cycloalkyl group;

each R¹¹And R¹²Independently is H, halogen, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together form a bond or together with the carbon atom to which they are attached form a substituted or unsubstituted C_3-8Cycloalkenyl or substituted or unsubstituted heterocyclyl;

Provided that the compound satisfies one of the following conditions (i) to (vi): (i) r¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；(ii)R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iii)R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iv)R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)；(v)R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-) according to the formula (I); and (vi) R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)。

In one variation, a compound of formula (a) is provided, applying any one or more (in one variation, all) of the following conditions (a) - (C):

(A) when R is^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3bAnd R^10bAt H, then: (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R¹¹Or R¹²Is an alkoxy group;

(B) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) is not substituted heteroaryl, and/or (ii) at least one R¹¹Or R¹²Is an alkoxy group; and

(C) when R is^2aAnd R^3aTogether form a methylene group (-CH) ₂-) or ethylene (-CH)₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2b、R^3b、R^10aAnd R^10bAt H, then: (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (ii) at least one R¹¹Or R¹²Is an alkoxy group.

The present invention also provides a compound of formula (II):

wherein:

R^2bis H, halogen or substituted or notSubstituted C₁-C₈An alkyl group;

each R^3aAnd R^3bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

p is 1 or 2;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m, and q are independently 0 or 1;

n is 1;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈PerhalogenationAlkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene group or a group of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group; and is

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, or acylamino.

Also provided is a compound of formula (B):

wherein:

R^2bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each R^10aAnd R^10bIndependently is H, halogen orSubstituted or unsubstituted C₁-C₈An alkyl group;

p is 1 or 2;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

each R^8a、R^8b、R^8cAnd R^8dIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C ₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-d)Together form a substituted or unsubstituted methylene group or a group of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-d)And the carbons to which they are attached together form a carbonyl or cycloalkyl group;

each R¹¹And R¹²Independently of each other is H, halogenAlkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together form a bond or together with the carbon atom to which they are attached form a substituted or unsubstituted C_3-8Cycloalkenyl or substituted or unsubstituted heterocyclyl; and is

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxy, carbonylalkoxy, aminocarbonylalkoxy, or acylamino.

In another aspect, the present invention provides a method of treating a cognitive, psychiatric, neurotransmitter-mediated or neuronal disorder in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I-1):

wherein:

R¹is H, hydroxy, nitro, cyano, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, perhaloalkyl, acyl, acyloxy, and the like,Carbonylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, mercapto, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R¹And R^10aTogether form a propylene (-CH) ₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^10aAnd R^10bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, hydroxy, alkoxy, cyano, nitro, or R^10aAnd R^10bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R ^10aAnd R¹Together form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^2aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R^10aAnd R^3aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

Each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

Each R⁴Independently H, hydroxy, nitro, cyano, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxyA carboxyl group, a carbonylalkoxy group, a mercapto group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a sulfanyl group, a substituted or unsubstituted amino group, an acylamino group, an aminoacyl group, an aminocarbonylamino group, an aminocarbonyloxy group, an aminosulfonyl group, a sulfonylamino group, a sulfonyl group, a carbonylalkylenealkoxy group, an alkylsulfonylamino group, or an acyl group;

m and q are independently 0 or 1;

n is 1;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C ₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C substituted by carbonylalkoxy, carboxy or acylamino₁-C₈Alkyl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene group or a group of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstitutedSubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, or acylamino;

provided that the compound satisfies one of the following conditions (i) to (vi): (i) r ¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；(ii)R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iii)R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iv)R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)；(v)R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-) according to the formula (I); and (vi) R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)。

It is to be understood that the variations and aspects described herein for one structural formula but which are applicable to another structural formula are equally applicable to the other structural formula as if each and every variation and aspect were specifically and individually listed. For example, when Q is specifically described in one structural formula, it should be understood that the same description of Q may apply to other structural formulas provided herein, if applicable (e.g., when such Q moieties are also present in other structural formulas). In addition, any preconditions or conditions described herein for one structural formula may also apply to other structural formulae, if applicable. For example, if applicable, conditions (a) - (G) of formula (I) in one aspect are equally applicable to formula (I-1) or any other structural formula described herein, as if each and all conditions were specifically and individually set forth.

The present invention also includes all salts, e.g., pharmaceutically acceptable salts, of the compounds referred to herein. The invention also includes any or all stereochemical forms of the compounds, as well as any tautomeric and equivalent forms, including any enantiomeric or diastereomeric form. Unless a stereochemical form is specifically indicated in a chemical structure or nomenclature, the structure or nomenclature includes all possible stereoisomers of the compound. In addition, when a specific stereochemical form is indicated, it is to be understood that the invention encompasses other stereochemical forms as well. The invention also includes all forms of the compounds, for example crystalline or amorphous forms of the compounds. The invention also relates to compositions comprising the compounds of the invention, such as compositions of substantially pure compounds, including specific stereochemical forms thereof. Compositions comprising mixtures of the compounds of the invention in any ratio are also encompassed by the invention, including mixtures of two or more stereochemically identical forms of the compounds of the invention, and thus also racemic, non-racemic, enantiomerically enriched (enantioenriched) and proportional (scalemic) mixtures of said compounds.

The invention also relates 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 encompassed by the invention. The compounds detailed herein or pharmaceutically acceptable salts thereof are also useful in the manufacture of a medicament for the treatment of cognitive, psychiatric, neurotransmitter-mediated disorders or neuronal disorders.

In one aspect, the compounds of the invention are useful for treating, preventing, delaying the onset and/or delaying the development of any one or more of the following in a subject in need thereof, such as a human: cognitive diseases, psychiatric diseases, neurotransmitter mediated diseases and/or neuronal diseases. In one variation, the compounds of the invention are useful for treating, preventing, delaying the onset of, and/or delaying the progression of a disease or condition for which modulation of an aminergic G protein-coupled receptor is believed to be beneficial. In one variation, the compounds of the invention are useful for treating, preventing, delaying the onset of, and/or delaying the progression of any one or more diseases or conditions for which neurosynaptic growth and/or neurogenesis and/or neurotrophic effects are believed to be beneficial. In another variation, the compounds of the invention are useful for treating, preventing, delaying the onset of, and/or delaying the progression of a disease or disorder for which modulation of aminergic G protein-coupled receptors and neuronal synaptic growth and/or neurogenesis and/or neurotrophic effects are believed to be beneficial. In one variation, the disease or condition is a cognitive disease, a psychiatric disease, a neurotransmitter-mediated disease, and/or a neuronal disease.

In another aspect, the compounds of the present invention for improving cognitive function and/or reducing psychotic effects in an individual comprise 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 another aspect, a compound of the invention for use in stimulating neuronal synaptic growth and/or promoting neurogenesis and/or enhancing a neurotrophic effect in an individual comprises administering to an individual in need thereof an amount of a compound described herein, or a pharmaceutically acceptable salt thereof, effective for stimulating neuronal synaptic growth and/or promoting neurogenesis and/or enhancing a neurotrophic effect. Loss of synapses is associated with a variety of neurodegenerative diseases and disorders, including alzheimer's disease, schizophrenia, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, stroke, head injury, and spinal cord injury. Compounds of the present invention that stimulate the growth of neuronal synapses may be beneficial in these situations.

In another aspect, a compound described herein is used for modulating an aminic 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 for modulating an aminic G protein-coupled receptor. In one variation, the compounds of the invention modulate at least one of the following receptors: adrenergic receptors (e.g. adrenergic receptors ，a_1D、a_2AAnd/or a_2B) Serotonin receptors (e.g., 5-HT)_2A、5-HT_2C、5-HT₆And/or 5-HT₇) Dopamine receptors (e.g., D)_2L) And histamine receptors (e.g., H)₁、H₂And/or H₃). In another variation, at least two of the following receptors are modulated: adrenergic receptors (e.g., a)_1D、a_2AAnd/or a_2B) Serotonin receptors (e.g., 5-HT)_2A、5-HT_2C、5-HT₆And/or 5-HT₇) Dopamine receptors (e.g., D)_2L) And histamine receptors (e.g., H)₁、H₂And/or H₃). In another variation, at least three of the following receptors are modulated: adrenergic receptors (e.g., a)_1D、a_2AAnd/or a_2B) Serotonin receptors (e.g., 5-HT)_2A、5-HT_2C、5-HT₆And/or 5-HT₇) Dopamine receptors (e.g., D)_2L) And histamine receptors (e.g., H)₁、H₂And/or H₃). In another variation, each of the following receptors is modulated: adrenergic receptors (e.g., a)_1D、a_2AAnd/or a_2B) Serotonin receptors (e.g., 5-HT)_2A、5-HT_2C、5-HT₆And/or 5-HT₇) Dopamine receptors (e.g., D)_2L) And histamine receptors (e.g., H)₁、H₂And/or H₃). In another variation, at least one of the following receptors is modulated: a is_1D、a_2A、a_2B、5-HT_2A、5-HT_2C、5-HT₆、5-HT₇、D_2L、H₁、H₂And H₃. In another variation, at least two, three, four, five, six, seven, eight, nine, ten, or eleven of the following receptors are modulated: a is_1D、a_2A、a_2B、5-HT_2A、5-HT_2C、5-HT₆、5-HT₇、D_2L、H₁、H₂And H₃. In a particular variant, at least a plurality is regulated Dopamine receptor D_2L. In another particular variant, at least dopamine receptor D is modulated_2LAnd serotonin receptor 5-HT_2A. In yet another specific variation, at least adrenergic receptor a_1D、a_2A、a_2BAnd serotonin receptor 5-HT₆Is adjusted. In another particular variant, at least adrenergic receptor a_1D、a_2A、a_2BSerotonin receptor 5-HT₆And one or more serotonin receptors 5-HT₇、5-HT_2A、5-HT_2CAnd histamine receptor H₁And H₂Is adjusted. In yet another specific variation, histamine receptor H is modulated₁. In another variation, the compounds of the invention exhibit modulatory activity at any of the receptors detailed herein, and also stimulate neuronal synaptic growth and/or neurogenesis and/or enhance neurotrophic effects.

The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. The invention also includes kits comprising a compound of the invention and instructions for use.

Detailed description of the invention

Definition of

The terms "a", "an", and the like, as used herein, refer to one or more than one unless clearly indicated otherwise.

Reference to "about" a value or parameter includes (and describes) embodiments that refer to the value or parameter itself. For example, a description referring to "about X" includes "X" itself.

The term "amine-capable G protein-coupled receptor" as used herein refers to a family of transmembrane proteins involved in cellular communication. Amine-enabled G protein-coupled receptors are activated by biogenic amines and represent a subset of the G protein-coupled receptor superfamily, which is structurally characterized by 7 transmembrane helices. The adrenergic G protein-coupled receptors include, but are not limited to, adrenergic receptors, serotonin receptors, dopamine receptors, histamine receptors, and imidazoline receptors.

The term "adrenergic receptor modulator" as used herein refers to and includes compounds that bind to or inhibit the binding of a ligand to an adrenergic receptor or that reduce or eliminate or increase or enhance or mimic the activity of an adrenergic receptor. Thus, "adrenergic receptor modulators" include adrenergic receptor antagonists and adrenergic receptor agonists. In some aspects, the adrenergic receptor modulator binds to or inhibits binding of the ligand to alpha in a reversible or irreversible manner₁Adrenergic receptors (e.g.. alpha.)_1A、α_1BAnd/or alpha_1D) And/or alpha₂Adrenergic receptors (e.g.. alpha.)_2A、α_2BAnd/or alpha_2C) And/or reduce or eliminate or increase or enhance or mimic alpha₁Adrenergic receptors (e.g.. alpha.) _1A、α_1BAnd/or alpha_1D) And/or alpha₂Adrenergic receptors (e.g.. alpha.)_2A、α_2BAnd/or alpha_2C) Activity of (2). In some aspects, the adrenergic receptor modulator inhibits ligand binding by at least about or about any one of the following values: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some aspects, an adrenergic receptor modulator reduces the activity of an adrenergic receptor by at least or about any of the following values, as compared to the corresponding activity prior to treatment with the adrenergic receptor modulator in the same individual, or as compared to the corresponding activity in other individuals not receiving the adrenergic receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some aspects, an adrenergic receptor modulator enhances the activity of an adrenergic receptor by at least about or any of the following values, as compared to the corresponding activity prior to treatment with the adrenergic receptor modulator in the same individual, or as compared to the corresponding activity in other individuals not receiving the adrenergic receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 95% or 100% or 200% or 300% or 400% or 500% or more. In some aspects, the adrenergic receptor modulator is capable of binding to an 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.

The term "dopamine receptor modulator" as used herein refers to and includes compounds that bind to or inhibit ligand binding to dopamine receptors or reduce or eliminate or increase or enhance or mimic dopamine receptor activity. Thus, "dopamine receptor modulators" include dopamine receptor antagonists and dopamine receptor agonists. In some aspects, dopamine receptor modulators bind to or inhibit ligand binding to dopamine-1 (D) in a reversible or irreversible manner₁) And/or dopamine-2 (D)₂) Receptors either reduce or eliminate or increase or enhance or mimic dopamine-1 (D)₁) And/or dopamine-2 (D)₂) The activity of the receptor. Dopamine D₂Receptors are divided into two classes: d_2LAnd D_2SThis is formed by different splicing of the individual genes. D_2LIntracellular domain ratio of receptor D_2SLong. In some embodiments, the dopamine receptor modulator inhibits ligand binding by at least about or about any of the following values: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, a dopamine receptor modulator reduces the activity of a dopamine receptor by at least about or any of the following values, as compared to the corresponding activity prior to treatment with the dopamine receptor modulator in the same individual, or as compared to the corresponding activity in other individuals who do not receive the dopamine receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, a dopamine receptor modulator enhances more than the corresponding activity in the same individual prior to treatment with the dopamine receptor modulator, or in other individuals who do not receive the dopamine receptor modulator At least about or about any of the following values for the activity of the barbamine receptor: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% or 200% or 300% or 400% or 500% or more. In some embodiments, the dopamine receptor modulator is capable of binding to an active site (e.g., a binding site for a ligand) of a dopamine receptor. In some embodiments, the dopamine receptor modulator is capable of binding to an allosteric site of a dopamine receptor.

The term "serotonin receptor modulator" as used herein refers to and includes compounds that bind to or inhibit ligand binding to serotonin receptors or reduce or eliminate or increase or enhance or mimic serotonin receptor activity. Thus, "serotonin receptor modulators" include serotonin receptor antagonists and serotonin receptor agonists. In some embodiments, the serotonin receptor modulator binds to or inhibits binding of the ligand to 5-HT in a reversible or irreversible manner_1AAnd/or 5-HT_1BAnd/or 5-HT_2AAnd/or 5-HT_2BAnd/or 5-HT_2CAnd/or 5-HT₃And/or 5-HT₄And/or 5-HT₆And/or 5-HT₇Receptors either reduce or eliminate or increase or enhance or mimic 5-HT_1AAnd/or 5-HT_1BAnd/or 5-HT _2AAnd/or 5-HT_2BAnd/or 5-HT_2CAnd/or 5-HT₃And/or 5-HT₄And/or 5-HT₆And/or 5-HT₇The activity of the receptor. In some embodiments, the serotonin receptor modulator inhibits at least about or about any one of the following values of ligand binding: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, a serotonin receptor modulator reduces the activity of the serotonin receptor by at least about or any of the following values as compared to the corresponding activity prior to treatment with the serotonin receptor modulator in the same individual, or as compared to the corresponding activity in other individuals not receiving the serotonin receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. At one endIn some embodiments, a serotonin receptor modulator enhances the activity of the serotonin receptor by at least about or any of the following values, as compared to the corresponding activity prior to treatment with the serotonin receptor modulator in the same individual, or as compared to the corresponding activity in other individuals not receiving the serotonin receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% or 200% or 300% or 400% or 500% or more. In some embodiments, the serotonin receptor modulator is capable of binding to an active site (e.g., a binding site for a ligand) of a serotonin receptor. In some embodiments, the serotonin receptor modulator is capable of binding to an allosteric site of a serotonin receptor.

The term "histamine receptor modulator" as used herein refers to a compound that binds to or inhibits the binding of a ligand to a histamine receptor or reduces or eliminates or increases or enhances or mimics the activity of a histamine receptor. Thus, "histamine receptor modulators" include histamine receptor antagonists and histamine receptor agonists. In some embodiments, the histamine receptor modulator binds to or inhibits binding of the ligand to histamine H in a reversible or irreversible manner₁Andor H₂And/or H₃Receptor reduction or elimination or increase or enhancement or mimicking of histamine H₁Andor H₂And/or H₃The activity of the receptor. In some embodiments, the histamine receptor modulator inhibits ligand binding by at least about or about any one of the following values: 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 the activity of the histamine receptor by at least about or any of the following values, as compared to the corresponding activity prior to treatment with the histamine receptor modulator in the same individual, or as compared to the corresponding activity in other individuals not receiving the histamine receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, compared to the corresponding activity prior to treatment with the histamine receptor modulator in the same individual, or The histamine receptor modulator enhances the activity of the histamine receptor by at least about or about any of the following values, as compared to the corresponding activity in other individuals who do not receive the histamine receptor modulator: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% or 200% or 300% or 400% or 500% or more. In some embodiments, the histamine receptor modulator is capable of binding to an 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 the histamine receptor.

Unless otherwise expressly stated, the term "subject" as used herein refers to a mammal, including but not limited to humans, bovine (bovine), primate, equine (equine), canine (Canine), feline (feline), porcine (porcine), and ovine (ovine). Thus, the invention is useful in the human pharmaceutical and veterinary contexts, including use in agricultural animals and domestic pets. The individual may be a human that has been diagnosed with or suspected of having a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder, and/or a neuronal disorder. The subject may be a human exhibiting one or more symptoms associated with cognitive, psychiatric, neurotransmitter-mediated disorders, and/or neuronal disorders. The subject may be a human having a mutant or abnormal gene associated with a cognitive disease, a psychiatric disease, a neurotransmitter-mediated disease, and/or a neuronal disease. The subject may be a human that is predisposed to cognitive, psychiatric, neurotransmitter-mediated, and/or neuronal disorders due to genetic or other causes.

As used herein, "treatment" refers to a method of achieving a beneficial or desired result, including a clinical result. In the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with a disease or disorder and/or diminishment of the extent of symptoms associated with a disease or disorder and/or prevention of worsening of symptoms associated with a disease or disorder. In one variation, the favorable or desired clinical outcome includes, but is not limited to, alleviation of symptoms associated with cognitive, psychiatric, neurotransmitter-mediated and/or neuronal disorders and/or lessening the extent of and/or preventing worsening of such symptoms. Preferably, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat a disease or condition with no or fewer side effects than those associated with currently available therapies for the disease or condition and/or to improve the quality of life of an individual.

As used herein, "delaying" the development of a disease or disorder refers to delaying, impeding, slowing, delaying, stabilizing and/or delaying the development of the disease or disorder. Such delay may be of varying length depending on the medical history and/or the individual receiving the treatment. It will be apparent to those skilled in the art that a sufficient or significant delay in an individual who does not develop the disease or condition may actually comprise prevention. For example, a method of "delaying" the progression of alzheimer's disease refers to a method that reduces the likelihood of progression of the disease within a given time frame and/or reduces the extent of the disease within a given time frame as compared to not using the method. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. For example, the development of alzheimer's disease can be detected using standard clinical techniques such as routine neurological examination, patient diagnosis, neuroimaging, detecting changes in the levels of specific proteins (e.g., amyloid peptides and Tau) in serum or cerebrospinal fluid, Computed Tomography (CT), or Magnetic Resonance Imaging (MRI). Similar techniques are known in the art for other diseases and conditions. Progression also refers to disease progression that may not be detectable at the outset and includes occurrence, recurrence and onset.

As used herein, an "at risk" individual refers to an individual at risk of developing a cognitive, psychiatric, neurotransmitter-mediated disorder and/or a neuronal disorder that can be treated with a compound of the present invention. An individual "at risk" may or may not have a detectable disease or disorder, may or may not exhibit a detectable disease prior to the treatment methods described herein. By "at risk" is meant that the individual has one or more so-called risk factors, which are measurable parameters that have a correlation with the development of a disease or condition, and are known in the art. Individuals with one or more of these risk factors are more likely to develop the disease or condition than individuals without these risk factors. These risk factors include, but are not limited to, age, sex, race, diet, past medical history, presence of precursor disease, genetic (i.e., hereditary) factors, and environmental exposure. For example, patients at risk for Alzheimer's disease include, for example, persons whose relatives have the disease and persons at risk as determined by genetic or biochemical marker analysis. Genetic markers of risk for alzheimer's disease include mutations in the APP gene, particularly the 717 position mutation and the 670 and 671 position mutations known as the hady (Hardy) and Swedish (Swedish) mutations, respectively (Hardy, Trends neurosci, 20: 154-9, 1997). Other risk indicators are a mutation in the presenilin gene (e.g., PS1 or PS2), the ApoE4 allele, a family history of alzheimer's disease, hypercholesterolemia, and/or atherosclerosis. Other such factors are also known in the art for other diseases and conditions.

The term "pro-cognitive" as used herein includes, but is not limited to, an improvement in one or more psychological processes, such as memory, attention, perception, and/or thinking, which can be assessed by methods known in the art.

The term "neurotrophic" effect as used herein includes, but is not limited to, effects that enhance neuronal function such as growth, survival and/or neurotransmitter synthesis.

The term "cognitive disease" as used herein relates to and refers to diseases and conditions which are believed to be or are actually involved in the progressive loss of neuronal structure and/or function (including neuronal death) or which are related thereto, and wherein a key feature of the disorder is impairment of cognition (e.g., memory, attention, perception and/or thinking). These disorders include pathogen-induced cognitive dysfunction, such as HIV-related cognitive dysfunction and lyme disease-related 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).

The term "psychiatric disorder" as used herein relates to and refers to a mental disease or condition which is believed to or does cause abnormal thinking and perception. Psychogenic disorders are characterized by a departure from reality and can be accompanied by delusions, hallucinations (meaning the perception in conscious and awake states in the absence of external stimuli, which have the characteristic of a real perception, in which case these sensations are vivid, distinct and located in an external objective space), personality changes and/or confusion. Other common symptoms include abnormal or bizarre behavior, as well as social interaction difficulties and impaired ability to perform daily activities. Exemplary psychiatric disorders are schizophrenia, bipolar disorder, psychosis, anxiety and depression.

The term "neurotransmitter-mediated disorder" as used herein relates to and refers to a disease or condition that is believed to be or is actually involved in or associated with a neurotransmitter such as histamine, serotonin, dopamine, an abnormal level of norepinephrine, or an impaired function of an aminergic G-protein coupled receptor. Exemplary neurotransmitter-mediated diseases include spinal cord injury, diabetic neuropathy, allergic diseases, and diseases involving age-protective (geroprotective) activity, such as age-related hair loss (hair loss), age-related weight loss, and age-related visual disorders (cataracts). Abnormal neurotransmitter levels are associated with a number of diseases and conditions including, but not limited to, alzheimer's disease, parkinson's disease, autism, gillbore syndrome, mild cognitive impairment, schizophrenia, ADHD, anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorder, psychosis, depression, and a variety of allergic disorders.

The term "neuronal disease" as used herein relates to and refers to a disease or condition which is believed to be or is actually involved in neuronal cell death and/or impaired or reduced neuronal function or which is associated with the above. Exemplary neuronal diseases 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's disease, Creutzfeldt-Jakob disease, Fahr disease, acute or chronic conditions associated with cerebral circulation such as ischemic or hemorrhagic stroke or other hemorrhagic damage, age-related memory impairment (AAMI), Mild Cognitive Impairment (MCI), mild cognitive impairment associated with trauma (MCI), post-concussion syndrome, post-traumatic stress disorder, adjuvant chemotherapy, Traumatic Brain Injury (TBI), neuronal death-mediated ocular diseases, macular degeneration, age-related macular degeneration, autism (including autism spectrum disorder), Asperger syndrome and Rett syndrome, Parkinson's disease, Avulsion injury, spinal cord injury, myasthenia gravis, gillandle syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, ADHD, anxiety, or depression.

The term "neuron" as used herein means a cell of ectodermal embryonic origin, derived from any part of the animal nervous system. Neurons express very characteristic neuron-specific markers including neurofilament protein, NeuN (neuronal nuclear marker), MAP2 and class III tubulin. Included as neurons are, for example, hippocampal neurons, cortical neurons, midbrain dopaminergic neurons, spinal cord motor neurons, sensory neurons, sympathetic neurons, septal cholinergic neurons, and cerebellar neurons.

The term "neurosynaptic growth" or "neurite activation" as used herein 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). Neuronal synapse growth or neurite activation may alter neural connectivity, leading to the establishment of new synapses or the remodeling of existing synapses.

The term "neurogenesis" as used herein refers to the generation of new neural cells from undifferentiated neuronal progenitor cells, also known as multipotent neuronal stem cells. Neurogenesis effectively generates new neurons, astrocytes, glia, schwann cells, oligodendrocytes, and/or other neural cell lines. Although neurogenesis persists to a later stage of life, it occurs in large numbers in the early stages of human development, particularly in certain localized areas of the adult brain.

The term "neural connectivity" as used herein refers to the number, type and nature of connections ("synapses") between neurons in an organism. Synapses form between neurons, between neurons and muscles ("neuromuscular junctions"), and between neurons and other biological structures, including internal organs, endocrine glands, and the like. Synapses have a specialized structure 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 function by establishing new synapses (e.g., by neuronal synaptic growth or neurite activation) or by altering or remodeling existing synapses. Synaptic remodeling refers to the change in the nature, intensity, or type of signal transmitted at a particular synapse.

The term "neuropathy" as used herein refers to a condition characterized by alterations in the function and/or structure of motor, sensory and autonomic neurons of the nervous system, which are caused or caused by a primary focus or other dysfunction of the nervous system. Types of peripheral neuropathies include polyneuropathy, mononeuropathy, mononeuritis multiplex, and autonomic neuropathy. The most common form is (symmetric) polyneuropathy, which mainly affects the feet and legs. Radiculopathy involves the spinal nerve root, but if peripheral nerves are also involved, the term radiculoneuropathy is used. The form of neuropathy can be further subdivided by the cause or size of the major fibers involved, such as large or small fiber peripheral neuropathy. Central neuropathic pain can occur from spinal cord injury, multiple sclerosis and certain strokes and fibromyalgia. Neuropathy can be accompanied by different combinations of weakness, changes in autonomy, and changes in sensation. Loss of muscle mass or spontaneous contraction of muscle bundles, a specific subtle muscle twitch, can also be seen. Sensory symptoms include loss of sensation and "positive" phenomena (including pain). Neuropathy is associated with a variety of conditions, including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiple sclerosis, and herpes zoster infection, as well as spinal cord injuries and other types of nerve damage.

The term "alzheimer's disease" as used herein refers to a degenerative brain disease that is clinically characterized by progressive memory loss, confusion, behavioral problems, inability to self-care, gradual physical deterioration and ultimately death. The disease is characterized histologically by neuritic plaques found primarily in the connective cortex, limbic system and basal ganglia. The main component of these plaques is the amyloid beta peptide (a β), which is the cleavage product of the beta amyloid precursor protein (β APP or APP). APP is a type I transmembrane glycoprotein comprising 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 produces several isoforms differing in the number of amino acids. A β appears to have a major role in neuropathology in alzheimer's disease. The familial form of the disease has been shown to be linked to mutations in the APP and presenilin genes (Tanzi et al, 1996, Neurobiol. Dis., 3: 159-168; Hardy, 1996, Ann. Med., 28: 255-258). Disease-associated mutations in these genes result in increased production of the 42-amino acid form of a β, 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 aboriginis antibodies: mechanisms abnormalities in Alzheimer's brain: conclusions), Ann Neurol, 2005, 57(5), 695-703; Wang et al, instruments-induced β -induced Mitochondrial dysfunction in Alzheimer's disease, Free Radiology & Medicine, 2007, 43, 1569-3; Swdlelerlerrier et al, Mitochondria in Alzheimer's disease (Mitochondria in Alzheimer's disease), Int. V.2002, Neoprene, 341, 23-1573; Swakerma et al, Mitochondria in research of Mitochondrial dysfunction in Alzheimer's disease), Regiondria et al, research of Mitochondrial dysfunction in Alzheimer's disease, Enteriov.618, research of Alzheimer's disease, research of Mitochondria, research, 3, research, etc.;. 23, research, diagnosis. Mitochondrial dysfunction has been proposed to have an etiologic relationship with neuronal function (including neurotransmitter synthesis and secretion) and viability. Thus, compounds that stabilize mitochondria can have beneficial effects in alzheimer's patients.

The term "huntington's disease" as used herein refers to a fatal neurological disease, the clinical characteristics of which are symptoms such as involuntary movement, cognitive impairment or loss of cognitive function and a broad spectrum of behavioral disorders. Common motor symptoms associated with huntington's disease include chorea (involuntary writhing and cramping), clumsiness, and progressive loss of walking, speaking (e.g., manifesting slurred speech), and swallowing ability. Other symptoms of huntington's disease may include cognitive symptoms such as loss of brain speed, attention and short-term memory, and/or behavioral symptoms, which may include personality changes, depression, irritability, emotional outbreaks, and apathy. Clinical symptoms typically occur in the fourth or fifth decade of life. Huntington's disease is a devastating and often long-term disease that usually dies about 10-20 years after symptoms appear. Huntington's disease is inherited through a mutated or abnormal gene encoding an abnormal protein called mutant Huntingtin protein; mutant huntingtin causes neuronal degeneration in many different brain regions. The degeneration focuses on neurons located in the basal ganglia, structures that control many important functions in the deep part of the brain, including coordination activities, and neurons on the outer surface of the brain or cortex that control thought, perception and memory.

As used herein, "amyotrophic lateral sclerosis" or "ALS" refers to a progressive neurodegenerative disease that attacks upper motor neurons (motor neurons in the brain) and/or lower motor neurons (motor neurons in the spinal cord) and causes motor neuron death. The term "ALS" as used herein includes all classifications of ALS known in the art including, but not limited to, classical ALS (usually affecting both lower and upper motoneurons), primary lateral sclerosis (PLS, usually affecting only upper motoneurons), progressive bulbar palsy (PBP or bulbar attack, which is a form of ALS that usually begins with difficulty swallowing, chewing and speaking), progressive muscular atrophy (PMA, usually affecting only lower motoneurons), and familial ALS (a hereditary form of ALS).

The term "parkinson's disease" as used herein refers to any medical condition in which an individual experiences one or more symptoms associated with parkinson's disease, such as (but not limited to) one or more of the following: resting tremor, rigidity in the gear, bradykinesia, postural reflex impairment, symptoms with good response to L-dopa therapy, absence of significant oculomotor palsy, cerebellar or pyramidal signs, muscular atrophy, dyskinesia, and/or language impairment. In a particular embodiment, the invention is used for the treatment of a condition associated with dopaminergic dysfunction. In a particular embodiment, the individual having parkinson's disease has a mutation or polymorphism in the synuclein, parkin or NURR1 nucleic acid (which is associated with parkinson's disease). In one embodiment, the subject having Parkinson's disease has a defective or reduced expression of a nucleic acid that modulates the development and/or survival of dopaminergic neurons or has a mutation in a nucleic acid.

The term "canine cognitive dysfunction syndrome" or "CCDS" as used herein refers to age-related deterioration of mental function characterized by multiple cognitive impairments affecting the ability of a diseased canine animal to function normally. The cognitive decline associated with CCDS cannot be entirely attributed to common medical conditions such as neoplasia, infection, sensory impairment or organ failure. Diagnosis of CCDS in canines such as dogs is often an exclusive diagnosis based on thorough behavioral and medical history and the presence of clinical symptoms of CCDS independent of other disease processes. Owner observation of age-related changes in behavior is a practical method for discovering possible episodes of CCDS in older domestic dogs. Many laboratory cognitive tasks can be used to help diagnose CCDS, while blood cell counts, chemical instrumentation and urinalysis can be used to rule out other underlying diseases that may be similar to the clinical symptoms of CCDS. Symptoms of CCDS include memory loss (which can be evidenced by disorientation and/or confusion in domestic dogs), reduced or altered interaction with family members and/or greeting behavior, altered sleep-wake cycles, reduced activity levels, and lost or frequent, inappropriate home training. Canines with CCDS may exhibit one or more of the following clinical or behavioral symptoms: reduced appetite, reduced awareness of the environment, reduced ability to recognize familiar locations, humans or other animals, hearing loss, reduced ability to ascend or descend stairs, reduced tolerance to autism, development of compulsive or repetitive behaviors or habits, circling, tremor or shaking, disorientation, reduced activity level, abnormal sleep-wake cycles, loss of family training, reduced or altered responsiveness to family members, and reduced or altered greeting behaviors. CCDS can significantly affect the health and well-being of diseased canines. Moreover, as CCDS becomes more severe and its symptoms become more severe, the partnership benefits brought by pets suffering from the disease become less.

The term "age-related memory impairment" or "AAMI" as used herein refers to a disorder of GDS phase 2 that can be identified on the Global Decline Scale (GDS) (Reisberg et al (1982) am. J. Psychiaatry 139: 1136-1139), which divides the aging process and progressive dementia into seven major stages. The first stage of GDS is the stage of objective evidence where individuals at any age have neither complaints nor impairments of cognitive impairment. These GDS stage 1 patients were considered normal. The second phase of GDS is applicable to those of the older age in general who complain of difficulties in memory and cognitive functions, such as wanting not to name but which can be done five or ten years ago, or wanting not to have them place things but which can be done five or ten years ago. These complaints appear very common in other normal elderly people. AAMI refers to GDS stage 2 humans, which may differ in neurophysiology from normal and unaddressed elderly (i.e., GDS stage 1). For example, AAMI individuals have been found to be electrophysiological slower on computer analyzed EEG than in GDS 1 aged people (Prichep, John, Ferris, Reisberg et al (1994) neurobiol. aging 15: 85-90).

The term "mild cognitive impairment" or "MCI" as used herein refers to a type of cognitive disorder characterized by a more pronounced deterioration in cognitive function than is normally shown for normal age-related decline. Thus, elderly or older people with MCI have greater difficulty performing complex daily tasks and learning than normal, but there are no other similar neurodegenerative disorders that typically do not perform normal daily social and/or professional functions in alzheimer's patients, or ultimately lead to dementia. MCI is characterized by mild, clinically significant impairment in cognition, memory and function, at levels insufficient to meet the diagnostic criteria for alzheimer's disease or other dementias. MCI also includes injury-related MCI, defined herein as cognitive impairment caused by certain types of injury, such as neurological injury (e.g., battlefield injury, including postconcussion syndrome, etc.), treatments for neurotoxicity (i.e., adjuvant chemotherapy resulting in "chemobrain," etc.), and tissue damage due to physical injury or other neurodegeneration, independent of and distinct from mild cognitive impairment caused by stroke, ischemia, hemorrhagic injury, blunt force trauma, etc.

The term "traumatic brain injury" or "TBI" as used herein refers to brain injury resulting from an abrupt trauma, such as a blow or jolt or penetrating head trauma, which disrupts brain function or destroys the brain. Symptoms of TBI can range from mild, moderate to severe, and can significantly affect many cognitive (language and communication, information processing, memory and perception skills deficits), physical (bed-exit activity, balance, coordination, fine motor, strength and endurance) and psychological skills.

"neuronal death-mediated ocular disease" refers to an ocular disease in which neuronal death is implicated, in whole or in part. The disease may involve death of photoreceptors. The disease may involve the death of retinal cells. The disease may involve death of the optic nerve by apoptosis. Specific neuronal death-mediated ocular diseases include, but are not limited to, macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Korotks disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Barbie syndrome, Erschel syndrome, blindness due to optic neuropathy, Leber hereditary optic neuropathy, achromatopsia, and Hansen-Larson-Berg syndrome.

The term "macular degeneration" as used herein includes all forms and categories of macular degeneration known in the art including, but not limited to, diseases characterized by progressive central vision loss associated with abnormalities of bruch's membrane, choroid, neuroretina and/or retinal pigment epithelium. The term thus includes conditions such as age-related macular degeneration (ARMD) as well as rare early onset dystrophies, which in some cases can be detected in the first decade of life. Other macular pathologies include north carolina macular dystrophy, sosbi fundus dystrophy, stargara disease, pattern-like dystrophy (pattern dystrophy), bestosis and Malattia Leventinese.

The term "autism" as used herein refers to a brain developmental disorder that impairs social interaction and communication and results in limited and repetitive behavior, usually occurring in infancy or early childhood. This cognitive and behavioral deficit is thought to be caused in part by alterations in neural connectivity. Autism includes related disorders sometimes referred to as "autism spectrum disorders" as well as asperger's syndrome and rett's syndrome.

The term "nerve injury" as used herein refers to physical damage to nerves, such as avulsion injury (i.e., where nerves have been torn or pulled apart) or spinal cord injury (i.e., damage to white matter or myelinated nerve fiber bundles that carry and transmit sensory and motor signals to and from the brain). Spinal cord injury can occur from a number of causes, including physical trauma (i.e., car accidents, sports injuries, etc.), tumors that invade the spine, developmental disorders such as spina bifida, etc.

The term "myasthenia gravis" or "MG" as used herein refers to a non-cognitive neuromuscular disorder resulting from an immune-mediated loss of acetylcholine receptors at the neuromuscular junction of skeletal muscle. Clinically, MG usually first appears as occasional muscle weakness in about two-thirds of patients, most commonly in the extraocular muscles. These initial symptoms eventually worsen, causing drooping eyelids (ptosis) and/or diplopia, often causing patients to seek medical assistance. Finally, many patients develop generalized muscle weakness, which may fluctuate weekly, daily, or even more frequently. Systemic MG often affects muscles that control facial expression, chewing, speaking, swallowing, and breathing; respiratory failure was the most common cause of death before recent advances in therapy.

The term "gillander syndrome" as used herein refers to a non-cognitive disease in which the body's immune system attacks a portion of the peripheral nervous system. The first symptoms of the disorder include a sensation of weakness or tingling in the legs to varying degrees. In many cases the weakness and stinging sensation spreads to the arms and upper body. These symptoms can increase in intensity until certain muscles are completely unusable and, when severe, the patient is almost completely paralyzed. The condition is life-threatening in these cases-potentially interfering with breathing and sometimes blood pressure or heart rate, and the disease is considered medically urgent. However, most patients recover from even the most severe gillbore syndrome, but some continue to have some degree of weakness.

The term "multiple sclerosis" or "MS" as used herein refers to an autoimmune disorder in which the immune system attacks the Central Nervous System (CNS), resulting in demyelination of neurons. It can cause a variety of symptoms, many of which are non-cognitive and often develop physical disabilities. MS affects areas of the brain and spinal cord known as white matter. When the processing is complete, white matter cells transmit signals between the gray matter region and the rest of the body. More specifically, MS destroys oligodendrocytes, cells that play a role in creating and maintaining a fatty layer (called the myelin sheath), which helps neurons carry electrical signals. MS results in thinning or complete loss of myelin and occasionally severing (transecting) the elongation or axon of neurons. When myelin is lost, neurons can no longer efficiently conduct their electrical signals. The disease can be associated with almost any neurological symptom. MS takes several forms, with new symptoms appearing in discrete episodes (recurrent forms) or slowly accumulating over time (progressive forms). Most people are first diagnosed with relapsing-remitting MS, but develop Secondary Progressive MS (SPMS) years later. Between episodes, symptoms may disappear completely, but persistent neurological problems often persist, especially as the disease progresses.

The term "schizophrenia" as used herein refers to a chronic psychotic disorder characterized by one or more positive symptoms (e.g., delusions and hallucinations) and/or negative symptoms (e.g., emotional lag 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, adolescent, chaotic, paranoid, residual or indeterminate schizophrenia and deficiency syndromes and/or in the american psychiatric association: diagnostic and Statistical Manual of Mental Disorders, fourth edition, Washington, 2000 or those described in International Statistical Classification of Diseases and related health issues, or others known to those skilled in the art.

"cognitive impairment associated with schizophrenia" or "CIAS" includes neuropsychological deficits in attention, working memory, language learning, and problem solving. These deficiencies are believed to be associated with impairment of functional status (e.g., social behavior, work performance, and activities of daily living).

The term "aging protective activity" or "aging protectant" as used herein means a biological activity that slows aging and/or prolongs life and/or increases or improves quality of life by reducing the level of quantity and/or intensity of pathologies or conditions that are not life-threatening but are associated with the aging process and typical for the elderly. Pathologies or conditions that are not life-threatening but are associated with the aging process include such pathologies or conditions as blindness (cataracts), degeneration (alopecia) of the dermopharmary integument with skin hairs, and age-related weight loss due to muscle and/or adipocyte death.

As used herein, Attention Deficit Hyperactivity Disorder (ADHD) is the neuropsychological disorder manifested in children of school age most frequently, affecting about 5-8% of the children in the population. ADHD refers to a chronic condition that manifests initially in childhood and is characterized by hyperactivity, impulsivity, and/or inattention. ADHD is characterized by a more extreme pattern of inattention and/or impulsivity-hyperactivity persisting than by observation of individuals at the same developmental level or stage. Considerable evidence has been derived from both family and twin studies, i.e., ADHD has a significant genetic component. The disorder is thought to be due to environmental interactions as well as genetic factors. ADHD includes all known ADHD types. For example, Diagnostic & Statistical Manual for Mental Disorders (DSM-IV) identified three ADHD subtypes: (1) ADHD, combined type, characterized by both inattention and hyperactivity-impulsivity symptoms; (2) ADHD, the primary inattentive type, characterized by inattention but no hyperactivity-impulsivity symptoms; and (3) ADHD, the major hyperactive-pulsatile type, characterized by hyperactivity-pulsatility but without inattention symptoms.

As used herein, Attention Deficit Disorder (ADD) refers to a disorder in the management of neurostimulation characterized by attention deficit and impulsivity, which can lead to uncontrollable behavior and can impair an individual's social, academic, or occupational function and development. ADD can be diagnosed by known methods, which can include observation behavior and diagnostic interview techniques.

The term "allergic disease" as used herein refers to a condition of the immune system characterized by over-activated mast and basophils and production of IgE immunoglobulins, resulting in a strong immune response. It represents one form of hypersensitivity to environmental substances known as allergens and is an acquired disease. Common allergic reactions include eczema, urticaria, hay fever, asthma, food allergies, reactions to the venom of stinging insects such as wasps and bees. Allergic reactions are accompanied by excessive release of histamine and can therefore be treated with antihistamines.

The term "combination therapy" as used herein refers to a therapy comprising two or more different compounds. Thus, in one aspect, there is provided a combination therapy comprising a compound as detailed herein and another compound. In some embodiments, 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 regimens employing combination therapy can produce additive or even synergistic (e.g., greater than additive) effects as compared to administration of the compounds of the invention alone. In some embodiments, each compound is used in a lesser amount as part of a combination therapy than the amount typically used for each compound alone. Preferably, the same or greater therapeutic benefit is obtained using combination therapy as compared to any of the individual compounds used alone. In some embodiments, the same or greater therapeutic benefit is achieved using a lesser amount of the compound (e.g., a lower dose or less frequent dosing regimen) in the combination therapy than is typically used with the compound alone or with the treatment alone. Preferably, the use of a lower dose of the compound results in a reduction in the number, severity, frequency and/or duration of one or more side effects associated with the compound.

The term "effective amount" as used herein refers to an amount of a compound of the invention that, in combination with its efficacy and toxicity parameters, should be effective in a given therapeutic modality as judged by the knowledge of the practitioner. An effective amount may be one or more doses, as understood in the art, e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single therapeutic agent may be considered to be a given effective amount if it is possible to obtain or obtain a desired or advantageous result in combination with one or more other therapeutic agents. Due to the combined effects (e.g., additive or synergistic effects) between the compounds, the appropriate dosage of any compound co-administered may optionally be reduced.

As used herein, "unit dosage form" refers to physically discrete units suitable as unitary 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 comprise single or combination therapies.

The term "controlled release" as used herein refers to a drug-containing formulation or a portion thereof in which the drug is not immediately released, i.e., administration of the "controlled release" formulation does not result in immediate release of the drug into the absorption cell. The term includes depot formulations designed to provide a gradual release of the drug compound over an extended period of time. Controlled release formulations can include a variety of drug delivery systems, typically including mixing a drug compound with a carrier, polymer, or other compound having a desired release profile (e.g., pH-dependent or non-pH-dependent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to the desired delivery route (e.g., coated capsules, implantable reservoirs, biodegradable capsules containing injection solutions, etc.).

As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" refers to materials that are not biologically or otherwise undesirable, e.g., the materials may be incorporated into a pharmaceutical composition for administration to a patient without causing any significant undesirable biological consequences or deleterious interaction with any of the other components included in the composition. The pharmaceutically acceptable carrier or excipient preferably has met the requisite standards for toxicological and pharmaceutical testing and/or is included in the American FDA's Manual of inert ingredients'.

"pharmaceutically acceptable salts" are those salts that retain at least some of the biological activity of the free (non-salt) compound and that can be administered to an individual as a medicament or pharmaceutical formulation. The pharmaceutically acceptable salt should be an ionic interaction, not a covalent bond. Thus, N-oxides are not considered salts. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; (2) salts formed by replacement of the acidic proton in the compounds of the invention with a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed by coordination 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 described in Berge et al, Pharmaceutical Salts, j.pharm.sci.1977, month 1; 66(1): 1-19. Pharmaceutically acceptable salts can be prepared in situ during manufacture, or by separately reacting the purified compound of the invention in free acid or free base form, respectively, with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed in a subsequent purification step. It will be understood that reference to a pharmaceutically acceptable salt includes the solvent addition form or a crystalline form thereof, particularly solvates or polymorphs. Solvates comprise stoichiometric or non-stoichiometric amounts of solvent and are often formed during crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical or electrical properties, stability and solubility. Factors such as recrystallization solvent, crystallization rate and storage temperature can cause a single crystal form to predominate.

The term "excipient" as used herein refers to an inert or inactive substance that can be used in the manufacture of a medicament or medicament, such as a tablet containing a compound of the invention as an active ingredient. The term excipient may include a variety of substances including, without limitation, any substance that acts as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, substance for chewable tablets, sweetener or flavoring agent, suspending/gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression/encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc ═ directly compressible), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, maltodextrin, carrageenan, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; substances used in chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

"alkyl" means and includes saturated straight, branched, or cyclic monovalent hydrocarbon structures and combinations thereof. Specific alkyl groups are those having from 1 to 20 carbon atoms ("C)₁-C₂₀Alkyl groups ") are used. More specific alkyl radicals are those having from 1 to 8 carbon atoms ("C)₁-C₈Alkyl groups ") are used. When referring to an alkyl group having a specified number of carbons, it is intended to include and describe all geometric isomers having that number of carbons; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, iso-butyl, tert-butyl, and cyclobutyl; "propyl" includes n-propyl, isopropyl and cyclopropyl. The termExemplified by the following groups: such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl, and the like. Cycloalkyl is a subset of alkyl groups and can form a ring such as cyclohexyl or multiple rings such as adamantyl. Cycloalkyl groups containing more than one ring may be fused, spiro, or bridged or combinations thereof. Preferred cycloalkyl groups are saturated cyclic hydrocarbons having from 3 to 13 ring carbon atoms. More preferred cycloalkyl groups are saturated cyclic hydrocarbons having from 3 to 8 ring carbon atoms ("C)₃-C₈Cycloalkyl "). Examples of cycloalkyl groups include adamantyl, decahydronaphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

"alkylene" refers to the same group as alkyl but having a divalent radical. Examples of alkylene groups include methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) butylene (-CH)₂CH₂CH₂CH₂-) and the like.

"alkenyl" means an unsaturated hydrocarbon group having at least one site of ethylenic unsaturation (i.e., having at least one group of the formula C ═ C), preferably having from 2 to 10 carbon atoms, more preferably having from 2 to 8 carbon atoms. Examples of alkenyl groups include, but are not limited to, -CH₂-CH＝CH-CH₃and-CH₂-CH₂Cyclohexenyl, wherein the ethyl group of the latter can be attached to the cyclohexenyl group at any available position on the ring.

Cycloalkenyl groups are a subset of alkenyl groups and can comprise one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. More preferred cycloalkenyl radicals are those having from 3 to 8 ring carbon atoms ("C)₃-C₈Cycloalkenyl group "). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

"alkynyl" means an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one group of the formula C ≡ C) and preferably having 2 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms.

"substituted alkyl" refers to an alkyl group having 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, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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 groups having 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, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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 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, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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 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) -, heterocycle-C (O) -and substituted heterocycle-C (O) -, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"acyloxy" refers to 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-, heterocycle-C (O) O-, and substituted heterocycle-C (O) O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted alkynyl, heteroaryl, substituted alkynyl, substituted aryl, substituted alkynyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having a single ring or multiple fused rings and having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms such as nitrogen, sulfur or oxygen. Heterocycles comprising more than one ring can be fused, spiro or bridged or any combination thereof. In fused ring systems, one or more rings may be aryl or heteroaryl. A heterocyclic ring having more than one ring wherein at least one ring is aromatic may be attached to the parent structure at a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocyclic ring having more than one ring wherein at least one ring is aromatic is attached to the parent structure at a non-aromatic ring position.

"substituted heterocycle" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 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, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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, the substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring can be aromatic or non-aromatic.

"aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), wherein the fused rings may or may not be aromatic. In one variation, the aryl group contains 6 to 14 ring carbon atoms. An aryl group having more than one ring, at least one of which is non-aromatic, may be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring, wherein at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

"heteroaryl" or "HetAr" refers to an unsaturated aromatic carbocyclic group having 2 to 10 ring carbon atoms and at least one ring heteroatom including, but not limited to heteroatoms such as nitrogen, oxygen and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl) where the fused rings may or may not be aromatic. Heteroaryl groups having more than one ring, at least one of which is non-aromatic, may be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring, wherein at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

"substituted aryl" refers to aryl groups 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, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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 heteroaryl having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, mercapto, alkylthio, 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 group in which the aryl moiety is attached to an alkyl group, and in which the aralkyl group may be attached to the parent structure either at the aryl or the alkyl group. Preferably, the aralkyl is attached to the parent structure through an alkyl group. "substituted aralkyl" refers to a group in which the aryl moiety is attached to a substituted alkyl group, and in which the aralkyl group may be attached to the parent structure either at the aryl or the alkyl group. When an aralkyl group is attached to the parent structure through an alkyl group, it is also referred to as "alkaryl". More specific alkylaryl groups are those arylalkyl groups ("C") having from 1 to 3 carbon atoms in the alkyl moiety ₁-C₃Alkaryl ").

"alkoxy" means an alkyl-O-group including, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1, 2-dimethylbutoxy, and the like. Similarly, alkenyloxy refers to "alkenyl-O-" and alkynyloxy refers to "alkynyl-O-". "substituted alkoxy" refers to substituted alkyl-O.

"unsubstituted amino" refers to-NH₂。

"substituted amino" refers to-NR_aR_bWherein (a) R_aAnd R_bEach independently selected from: H. alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, with the proviso that R is_aAnd R_bThe groups are not all H; or (B) R_aAnd R_bTogether with the nitrogen atom, form a heterocyclic or substituted heterocyclic ring.

"acylamino" refers to the group-C (O) NR_aR_bWherein R is_aAnd R_bIndependently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, or R_aAnd R_bThe groups can form a heterocyclic or substituted heterocyclic ring with the nitrogen atom.

"aminocarbonylalkoxy" refers to-NR_aC(O)OR_bWherein R is_aAnd R_bEach independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle.

"aminoacyl" refers to-NR_aC(O)R_bWherein R is_aAnd R_bEach independently selected from H, alkyl, substituted alkyl, alkenyl, substitutedAlkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle. Preferably R_aIs H or alkyl.

"aminosulfonyl" means-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 ring and-NRSO₂-substituted heterocycle, wherein 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, heterocycle, and substituted heterocycle are as defined herein.

"Sulfonylamino" means-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-heterocycles and-SO₂NR-substituted heterocycles wherein R is H or alkyl, or-SO₂NR₂Wherein two R groups together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring.

"Sulfonyl" means-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-heterocycle and-SO₂-a substituted heterocycle.

"Carbonylalkylenealkoxy"Refers to-C (═ O) - (CH)₂)_n-OR, wherein R is a substituted OR unsubstituted alkyl group and n is an integer from 1 to 100, more preferably n is an integer from 1 to 10 OR from 1 to 5.

"halo" or "halogen" refers to an element of group 17 having an atomic number of 9 to 85. Preferred halogen groups include fluoro, chloro, bromo and iodo groups. When a group is substituted with more than one halogen, the group can be described using a prefix corresponding to the number of halogens attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc., referring to aryl and alkyl groups substituted with two ("di") or three ("tri") halogen groups, which can be, but are not necessarily, the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl groups. Alkyl groups in which each H is replaced by a halogen are referred to as "perhaloalkyl groups". Preferred perhaloalkyl groups are trifluoroalkyl (-CF) ₃). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H in the hydrocarbon making up the alkyl portion of the alkoxy group is substituted with a halogen. An example of perhaloalkoxy is trifluoromethoxy (-OCF)₃)。

"carbonyl" refers to C ═ O.

"cyano" means-CN.

"oxo" refers to ═ O.

"nitro" means-NO₂。

"alkylthio" refers to-S-alkyl.

"Alkylsulfonylamino" refers to-R¹SO₂NR_aR_bWherein R is_aAnd R_bIndependently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, or R_aAnd R_bTogether with the nitrogen atom form a heterocyclic or substituted heterocyclic ring, and R¹Is an alkyl group.

"carbonylalkoxy" as used herein means-C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-alkenyl, -C (O) O-substituted alkenyl, -C (O) O-alkynyl, -C (O) O-substituted alkynyl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, or-C (O) O-substituted heterocycle.

"twin" refers to the relationship of two groups attached to the same atom, for example, in the group-CH₂-CHR¹R²In, R ¹And R²Is geminal and R¹May be referred to as R²Twin R groups of (a).

"vicinal" refers to the relationship between two radicals attached to adjacent atoms. For example, in the group-CHR¹-CH₂R²In, R¹And R²Is vicinal and R¹May be referred to as R²Vicinal R radical of (1).

By a composition of a "substantially pure" compound is meant that the composition comprises 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% of impurities, which may be different stereochemical forms of the compound. For example, a composition of substantially pure S-form 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 compound of R-form.

Compounds of the invention

The compounds of the present invention are described in detail herein, including in the summary, and claims. The present invention includes the use of all of the compounds described herein, including any and all stereoisomers, salts and solvates of said compounds, as histamine receptor modulators.

The present invention includes compounds of formula (I) or salts or solvates thereof:

wherein:

R¹is H, hydroxy, nitro, cyano, halogen, substituted or unsubstituted C ₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, mercapto, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each R^2aAnd R^2bIndependently is H, substituted or unsubstituted C₁-C₈Alkyl, halogen, cyano, hydroxy, alkoxy, nitro, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a carbonyl or cycloalkyl group, or R^2aAnd R¹Together forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-, or R ^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

Each R⁴Independently of each other is H, hydroxyRadical, nitro radical, cyano radical, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C ₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxy, carboxyl, carbonylalkoxy, mercapto, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, sulfanyl, 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 R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C substituted with carbonylalkoxy, carboxy or acylamino₁-C₈Alkyl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R ^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bondProvided that when R is^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

provided that the compound satisfies one of the following conditions (i) to (vi): (i) r¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；(ii)R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iii)R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iv)R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)；(v)R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-) according to the formula (I); and (vi) R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)；

And the premise is that:

(A) when R is¹And R^3aTogether form a propylene (-CH) ₂CH₂CH₂-, the following conditions (a) to (d) apply: (a) when each X is⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H), X⁹Is CR⁴(wherein R is⁴Is H or methoxy), each q and m is 0, n is 1 and each R^8eAnd R^8fWhen H, Q is not phenyl, (b) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each q, m and n is 1 and each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not dimethylamino, (c) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not pyrrolidin-1-yl, and (d) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each of q and m is 0, n is 1 and R^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group;

(B) when R is¹And R^3aTogether form butylene (-CH)₂CH₂CH₂CH₂-) and each X⁷-X¹⁰Is CR⁴(wherein R is⁴In the case of H), the conditions (f) to (k) apply: (f) when each of q, m and n is 1 and each R is^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen it is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl which is not substituted azetidinyl, alkoxy, carbonylalkoxy or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R^8a、R^8b、R^8cAnd R^8dIs H and R^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not a substituted amino group of the formula-NHR, wherein R is substituted alkyl, (h) when Q is 0, each of m and n is 1 and R is ^8c、R^8d、R^8eAnd R^8fWhen H, Q is not carboxy and an acylamino group of the formula-C (O) NHR, wherein R is substituted alkyl, (i) Q is 0, each m and n is 1, each R is^8cAnd R^8dIs H andR^8eand R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not methoxy and cyclopentylamino, (j) when each Q and m is 0, n is 1 and each R is^8eAnd R^8fWhen H, Q is not phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino [ -C (O) NH-cyclopentyl substituted by cyclopentyl]And (k) when each of q and m is 0, n is 1 and R is^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group;

In another variation, the compound of formula (I) is as described above, with the proviso that in addition to conditions (a) - (C), conditions (D), (E), (F), and (G) also apply:

(D) when R is^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3bAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl;

(E) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R ^2a、R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl; and

(F) when R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-f)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl; and

(G) when R is¹And R^3aTogether form butylene (-CH)₂CH₂CH₂CH₂-, q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not cyano.

In one variation, the compound of formula (I) has one or more of the following structural features: (1) x⁷、X⁸、X⁹And X¹⁰At least one of which is N; (2) r present⁸Is not H (e.g., when q, m and n are all 1, at least one R is^8a-R^8fNot H, e.g. at least one R⁸The moiety is alkyl, alkoxy or hydroxy); (3) q is not substituted heteroaryl; and (4) R¹Is substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or acyl. In a particular variant of formula (I), X⁷、X⁸、X⁹And X¹⁰At least one of which is N, R being present⁸At least one of the moieties is not H (e.g., hydroxy or methyl). In another variant of formula (I), X⁷、X⁸、X⁹And X¹⁰At least one of which is N, each R present⁸Part is H. In a variant of formula (I), X ⁷、X⁸、X⁹And X¹⁰Is N, Q is not substituted heteroaryl, R is present⁸The moieties are all H, or at least one R present⁸Moieties are not H.

In one variation, there is provided a compound of formula (I), wherein at least one R^8(a-f)Is substituted C₁-C₈Alkyl radical, wherein C₁-C₈Alkyl is substituted with carbonylalkoxy, carboxy, or acylamino.

In another variant of formula (I), at least one R^3aAnd R^3bIs an aryl group. In a particular variant of formula (I), at least one R^3aAnd R^3bIs phenyl.

In another variation, a compound of formula (I) is provided, wherein conditions (ii) and (iii) are not applicable, and one of conditions (I) and (iv) - (vi) is applicable. In another variation, a compound of formula (I) is provided, wherein condition (ii) does not apply, and one of conditions (I) and (iii) - (vi) applies. In another variation, a compound of formula (I) is provided, wherein condition (iii) does not apply, and one of conditions (I), (ii), and (iv) - (vi) applies.

In one variation, there is provided a compound of formula (I), wherein condition (I) applies such that R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-). In another variation, there is provided a compound of formula (I), wherein m is 0 and q is 1; x ⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H); x⁹Is CR⁴(wherein R is⁴Is substituted or unsubstituted alkyl or halogen, the condition (ii) being applied such that R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (I), wherein m is 0 and q is 1; x⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H); x⁹Is CR⁴(wherein R is⁴Is substituted or unsubstituted alkyl or halogen, the condition (iii) being applied such that R is¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (I), wherein condition (iv) applies such that R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-). In one variation, there is provided a compound of formula (I), wherein condition (v) applies such that R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (I), wherein condition (vi) applies such that R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-). In any of conditions (i) - (v), a 5-membered ring is provided in one variation by said conditions, e.g., when R is as in condition (i)¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) are also provided. In one variation the 5-membered ring is provided by the conditions, e.g. when R is as in condition (i) ¹And R^2aTogether form a propylene (-CH)₂CH₂CH₂-) are also provided.

There is provided a compound of formula (I) wherein at least one of m and q is 1 and at least one X⁷、X⁸、X⁹And X¹⁰Is CR⁴Wherein R is⁴Not being H, e.g. R⁴Is methyl or halogen. In one aspect, there is provided a compound of formula (I) wherein at least one of m and q is 1, at least one X⁷、X⁸、X⁹And X¹⁰Is CR⁴(wherein R is⁴Is not H) and R¹And R^3aTogether form a propylene group. The compounds herein may also be of formula (I) wherein X⁹Is CR⁴Wherein R is⁴Is substituted or unsubstituted alkyl or halogen. In one such variant, X⁹Is CR⁴(wherein R is⁴Is substituted or unsubstituted alkyl or halogen, m and Q are both 0 and Q is substituted or unsubstituted aryl, such as phenyl. In another such variation, X⁹Is CR⁴(wherein R is⁴Is substituted or unsubstituted alkyl or halogen) and R¹And R^3aTogether form a propylene group. In another such variation, X⁹Is CR⁴(wherein R is⁴Is substituted or unsubstituted alkyl or halogen) and R¹And R^10aTogether form a propylene group. Also provided are compounds of formula (I) wherein at least one of m and q is 0. In one aspect, there is provided a compound of formula (I) wherein m, Q and n are each 1 and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, or acylamino.

Also provided are methods of using the compounds described herein, e.g., compounds of formula (I), in various therapeutic applications. Also provided are methods of using compounds of formula (I-1) or salts or solvates thereof:

wherein:

R¹is H, hydroxy, nitro, cyano, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, mercapto, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-, or R ¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-, or R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；

Each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C ₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group; and is

Compounds detailed herein, for example compounds 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), (A1) - (A4), (B1) - (B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, are useful as novel histamine receptor modulators. The compounds of the invention may also be useful in the treatment of neurodegenerative diseases.

In another variation, the invention includes compounds described herein, such as compounds of formulas (I) - (VII), (I-1), (Ia) - (Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa) - (IIk), (IIi-1), (A1) - (A4), (B1) - (B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4 or any variation or salt or solvate thereof. In a particular variation, the invention includes methods of using the compounds described herein, for example, compounds 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), (A1) - (A4), (B1) - (B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4 as detailed herein or any of the variations thereof or salts or solvates thereof herein.

In one variation, the invention includes compounds described herein, for example compounds of formulas (I) - (VII), (I-1), (Ia) - (Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), (Ii-7), (IIa) - (IIk), (IIi-1), (A1) - (A4), (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 salt or solvate herein. In another variation, the invention includes methods of use and administration of the compounds described herein, for example, compounds 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), (A1) - (A4), (B1) - (B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4 as detailed herein or any of the variations thereof or salts or solvates thereof herein.

In one variation, the invention includes compounds of formulae (Ia) - (Ih):

wherein X⁷、X⁸、X⁹、X¹⁰、R¹、R^2a、R^2b、R^3a、R^3b、R^8a、R^8b、R^8c、R^8d、R^8e、R^8f、R^10a、R^10bQ, p, m and Q, if present, are as defined for formula (I);

each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C ₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylaminoA sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino moiety;

s is an integer of 0 to 5; and is

t is an integer of 0 to 4.

In one variation, compounds of formulae (Ia) - (Ih) are provided, wherein for each structural formula: (A) at least one X⁷-X¹⁰Is N; and/or (B) at least one R, if present⁸Moiety (at least one R)^8a、R^8b、R^8c、R^8d、R^8eAnd R^8f) Is hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In one such variation, compounds of formulae (Ia) - (Ie) and (Ig) - (Ih) are provided wherein for each formula, at least one X is⁷-X¹⁰Is N and each R present⁸All fractions are H. In another variation, compounds of formulas (Ia) - (Ie) and (Ig) - (Ih) are provided wherein for each formula at least one R is present ⁸Moiety (R)^8a、R^8b、R^8c、R^8d、R^8eAnd R^8f) Is hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In a particular variation, compounds of formulas (Ia) - (Ie) and (Ig) - (Ih) are provided wherein at least one R is^8eAnd R^8fIs hydroxyl or methyl. In one aspect, when at least one R is^8eAnd R^8fWhen it is hydroxy or methyl, each X⁷-X¹⁰Is CR⁴. In another variation, compounds of formulas (Ia) - (Ie) and (Ig) - (Ih) are provided wherein R is^8eIs hydroxy and R^8fIs methyl.

In one variation, the invention includes any one or more of the compounds of formulas (Ib), (Ie), (Ii), (Ij) and (Ik):

wherein: q, X⁷、X⁸、X⁹、X¹⁰、R⁴、R¹、R^2a、R^2b、R^3a、R^3b、R^10a、R^10b、R^8c、R^8d、R^8eAnd R^8fIf present, as defined by formula (I); and is

Wherein each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, or aminocarbonylamino;

s is an integer of 0 to 5; and is

t is an integer of 0 to 4.

In one variation, the invention includes compounds of formula (Ii-1):

wherein X⁷、R¹、R^2a、R^2b、R^3a、R^3b、R^10aAnd R^10bAs defined for formula (I);

R⁴is halogen (e.g., chloro) or alkyl (e.g., methyl), ethyl, i-propyl, or t-butyl;

R^8eand R^8fIndependently H, OH or CH₃(ii) a And is

Q is substituted or unsubstituted aryl or heteroaryl;

the premise is that: (i) when X is present⁷When is N, R^8eAnd R^8fIs H; and (ii) when X⁷Is CR⁴(wherein R is⁴Is H), R^8eIs OH and R^8fIs H or CH₃. In embodiments of formula (Ii-1), Q is a substituted or unsubstituted pyridyl.

In one variation of formula (Ii-1), R⁴Is halogen. In one aspect, when R⁴When it is halogen, it is chlorine. In another variation of formula (Ii-1), R⁴Is C₁-C₄Alkyl groups such as methyl, ethyl, propyl or butyl. In another variation of formula (Ii-1), R¹Is H or substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl).

In one variation, the invention includes any one or more of the compounds of formulae (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6), and (Ii-7):

wherein R is¹、R^2a、R^2b、R^3a、R^3b、R^10aAnd R^10bAs defined for formula (I);

R⁴is halogenElements (e.g. chlorine) or alkyl (e.g. CH)₃Ethyl, isopropyl or tert-butyl);

R⁹Is H or CH₃(ii) a And is

R^8fIs H or CH₃。

In one variation of formulae (Ii-2) - (Ii-7), R⁴Is halogen. In one aspect, when R⁴When it is halogen, it is chlorine. In another variation of formulas (Ii-2) - (Ii-7), R⁴Is C₁-C₄Alkyl groups such as methyl, ethyl, propyl or butyl. In one variation of formulae (Ii-2) - (Ii-7), R¹Is H or substituted or unsubstituted C₁-C₈An alkyl group.

In one variation, compounds of formula (Ii-3) are described, provided, in one aspect, that R^2aAnd R^3aNot together forming a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-, provided that R is^3aAnd R^10aNot together forming ethylene (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)。

Although R of formula (Ii-2), (Ii-3), (Ii-5) and (Ii-6)⁹Attached to a particular position of the pyridyl group, in other embodiments, analogous structures are provided, wherein R⁹To the pyridyl ring at any available carbon atom. Similarly, although R of formula (Ii-4) and (Ii-7)⁹Can be attached at any available position on the pyridyl ring, and in other embodiments, similar independent structures are provided wherein R is⁹May be individually connected to each such available location.

The invention also includes a compound of formula (a) or a salt or solvate thereof:

wherein:

R¹、R^2a、R^2b、R^3a、R^3b、R^10a、R^10b、X⁷、X⁸、X⁹、X¹⁰m and q are as defined for formula (I);

Each R^8a、R^8b、R^8cAnd R^8dIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-d)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-d)And the carbons to which they are attached together form a carbonyl or cycloalkyl group; and

each R¹¹And R¹²Independently is H, halogen, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together form a bond or together with the carbon atom to which they are attached form a substituted or unsubstituted C_3-8Cycloalkenyl or substituted or unsubstituted heterocyclyl moieties;

provided that the compound satisfies one of the following conditions (i) to (vi): (i) r¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-C) H₂CH₂CH₂-)；(ii)R¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iii)R¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)；(iv)R^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)；(v)R^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-) according to the formula (I); and (vi) R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)。

Or a pharmaceutically acceptable salt thereof.

In one variation, a compound of formula (a) is provided, wherein the following conditions (a) - (C) apply:

(A) when R is^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3bAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R¹¹Or R¹²Is an alkoxy group;

(B) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxyAnd/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R¹¹Or R¹²Is an alkoxy group; and

(C) when R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R ¹¹Or R¹²Is an alkoxy group;

or a pharmaceutically acceptable salt thereof.

In one variation, there is provided a compound of formula (a), wherein at least one R^8(a-f)Is substituted C₁-C₈Alkyl radical, wherein said C₁-C₈Alkyl is substituted with carbonylalkoxy, carboxy, or acylamino.

In another variant of formula (A), at least one R^3aAnd R^3bIs an aryl group. In a particular variant of formula (A), at least one R^3aAnd R^3bIs phenyl.

In another variant of formula (A), each R¹¹And R¹²Independently is H, halogen, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together forming a bond.

In one variation, a compound of formula (A) is provided, whichIn (ii) so that R is¹And R^2aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-). In another variation, there is provided a compound of formula (a), wherein condition (ii) applies such that R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (a), wherein condition (iii) applies such that R is ¹And R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (a), wherein condition (iv) applies such that R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-). In one variation, there is provided a compound of formula (a), wherein condition (v) applies such that R is^2aAnd R^10aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-). In another variation, there is provided a compound of formula (a), wherein condition (vi) applies such that R^3aAnd R^10aTogether forming an ethylene radical (-CH)₂CH₂-) or propylene (-CH)₂CH₂CH₂-). In any variation of formula (a) detailed herein, where applicable, the structural formula can also be defined, in one aspect, by one or more of the following structural features: x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Is substituted or unsubstituted C₁-C₈Alkyl or halogen; q is 0 and m is 1; each R^8a、R^8B、R^8cAnd R^8dIf present, are all H; at least one R¹¹And R¹²Is substituted or unsubstituted C₁-C₈An alkyl group.

In a variant of formula (A), R¹¹Is H, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₁-C₈Perhaloalkyl radical, R ¹²Is H, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₁-C₈Perhaloalkyl, or with R¹¹And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈A cycloalkenyl moiety.

The present invention also includes compounds of formula (a1), (a2), (A3), and (a 4):

wherein R is¹、R^2a、R^2b、R^3a、R^3b、R^8a、R^8b、R^8c、R^8d、R^10a、R^10b、R¹¹、R¹²、X⁷、X⁸、X⁹、X¹⁰Q, m and q are as defined for formula (A).

In one variation, compounds of formulae (a1), (a2), (A3), and (a4) are provided, where one or more (in one variation, all) of the following conditions (a) - (C) apply:

(B) when R is¹And R^3aTogether form a propylene (-CH)₂CH₂CH₂-) or butylene (-CH)₂CH₂CH₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R¹¹Or R¹²Is an alkoxy group; and

(C) when R is^2aAnd R^3aTogether form a methylene group (-CH)₂-) or ethylene (-CH)₂CH₂-)，X⁷-X¹⁰Is CR⁴Each R ^2b、R^3b、R^10aAnd R^10bWhen H, then (i) at least one R^8(a-d)Is hydroxy, alkyl or alkoxy, and/or (ii) Q is not substituted heteroaryl, and/or (iii) at least one R¹¹Or R¹²Is an alkoxy group.

All variables relating to the formulae (I) and (A) may, if appropriate, likewise be applied to any of the formulae provided herein, for example, any of formulas (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), (B1) - (B4), (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4, as if each and all of the variables were specifically and individually listed.

In another variation, the invention includes a compound of formula (II) or a salt or solvate thereof:

wherein:

R^2bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

each R⁴Independently H, hydroxy, nitro, cyano, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C ₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxy, carboxyl, carbonylalkoxy, mercapto, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino, or acyl;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C ₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group; and

In one variation, each R⁴Independently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group.

In one variation, there is provided a compound of formula (II), wherein at least one R^8(a-f)Is substituted C₁-C₈Alkyl radical, wherein said C₁-C₈Alkyl is substituted with carbonylalkoxy, carboxy, or acylamino. In one aspect of formula (II), p is 1. In a particular aspect of formula (II), p is 1 and X⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H. In one such aspect of formula (II), p is 1; x⁷、X⁸And X¹Is CR⁴(wherein R is ⁴Is H) and X⁹Is CR⁴(wherein R is⁴Is unsubstituted C₁-C₈Alkyl, for example methyl, or halogen, such as chlorine). In another variant of formula (II), p is 1; x⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Is unsubstituted C₁-C₈An alkyl group; q is 0. In another variant of formula (II), p is 1; q is 0; m is 1 and R^8cAnd R^8dAre all H. In another variant of formula (II), p is 1; q is 0; m is 1; r^8cAnd R^8dAre all H and R^8eAnd R^8fIndependently is H, hydroxy, unsubstituted C₁-C₈Alkyl groups, or together with the carbon to which they are attached, form an unsubstituted methylene or carbonyl moiety. In one variant of formula (II), p is 1; q is 0; m is 1; r^8eAnd R^8fAre all H and R^8cAnd R^8dIndependently is H, hydroxy, unsubstituted C₁-C₈Alkyl groups, or together with the carbon to which they are attached, form an unsubstituted methylene or carbonyl group. In another variant of formula (II), p is 1; q is 0; m is 1; r^8eAnd R^8cTogether form a bond and R^8dAnd R^8fIndependently of each other is H, unsubstituted C₁-C₈Alkyl, or together form a bond, to obtain an acetylene moiety. In another aspect of formula (II), p is 2. In any of the variations detailed herein, the compound may be further defined by one or both of the following structural features, if applicable: x ⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H) and X⁹Is CR⁴(wherein R is⁴Is unsubstituted C₁-C₈Alkyl groups).

In one variation, the invention includes compounds of formulae (IIa) to (IIh):

wherein X⁷、X⁸、X⁹、X¹⁰、R^2b、R^3a、R^3b、R^8a、R^8b、R^8c、R^8d、R^8e、R^8f、R^10a、R^10bQ, m, p and as defined for formula (II);

each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈An alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, or aminocarbonylamino moiety;

s is an integer of 0 to 5; and

t is an integer of 0 to 4.

In one variation, the invention includes any one or more of the compounds of formulae (IIb), (IIe), (IIi), (IIj), and (IIk):

q, X therein⁷、X⁸、X⁹、X¹⁰、R⁴、R^2b、R^3a、R^3b、R^8c、R^8d、R^8e、R^8fAnd p, if present, is as defined for formula (II);

s is an integer of 0 to 5; and

t is an integer of 0 to 4.

In one variation, the invention includes compounds of formula (IIi-1):

wherein X⁷、R^2b、R^3a、R^3b、R^10aAnd R^10bAs defined for formula (I);

R⁴is halogen (e.g. chlorine) or alkyl (e.g. CH)₃Ethyl, isopropyl or tert-butyl);

R^8eand R^8fIndependently H, OH or CH₃(ii) a And

q is substituted or unsubstituted aryl or heteroaryl;

the premise is that: (i) when X is present⁷When is N, R^8eAnd R^8fIs H; (ii) when X is present⁷Is CR⁴(wherein R is⁴Is H), R^8eIs OH and R^8fIs H or CH₃. In one embodiment of formula (IIi-1), Q is substituted or unsubstituted pyridyl.

In a variant of formula (IIi-1), R⁴Is halogen. In another variation of formula (IIi-1), R⁴Is C₁-C₄An alkyl group.

The invention also includes a compound of formula (B) or a salt or solvate thereof:

wherein:

R^2b、R^3a、R^3b、R^10a、R^10b、X⁷、X⁸、X⁹、X¹⁰m, p and q are as defined for formula (II);

each R^8a、R^8b、R^8cAnd R^8dIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C partially substituted with carbonylalkoxy, carboxy or acylamino ₁-C₈Alkyl, or geminal R^8(a-d)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-d)And the carbons to which they are attached together form a carbonyl or cycloalkyl group;

each R¹¹And R¹²Independently is H, halogen, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted orUnsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together form a bond or together with the carbon atom to which they are attached form a substituted or unsubstituted C_3-8Cycloalkenyl or substituted or unsubstituted heterocyclyl.

In one variation, there is provided a compound of formula (B), wherein at least one R^8(a-f)Is substituted C₁-C₈Alkyl radical, wherein said C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

In another variant of formula (B), each R¹¹And R¹²Independently is H, halogen, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C ₂-C₈Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈A perhalogenated alkyl group, a halogen atom,the bond indicates the presence of an E or Z double bond configuration, or R¹¹And R¹²Together forming a bond.

In another variant of formula (B), R¹¹Is H, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₁-C₈Perhaloalkyl radical, R¹²Is H, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₁-C₈Perhaloalkyl, or with R¹¹And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈A cycloalkenyl moiety.

The invention also includes compounds of formulae (B1), (B2), (B3), and (B4):

wherein R is^2b、R^3a、R^3b、R^8a、R^8b、R^8c、R^8d、R^10a、R^10b、R¹¹、R¹²、X⁷、X⁸、X⁹、X¹⁰Q and p are as defined for formula (B).

In one variant of formula (B), m is 0 and q is 1. In another variant of formula (B), m is 0, q is 1 and at least one R is¹¹And R¹²Is unsubstituted C₁-C₈Alkyl (e.g., methyl). In another variant of formula (B), m is 0, q is 1, R¹¹Is H and R¹²Is H. In one aspect of formula (B), m is 0, q is 1, at least one R¹¹And R¹²Is unsubstituted C₁-C₈Alkyl and X⁷、X⁸And X¹⁰Are all CR⁴(wherein R is⁴Is H). In one aspect of formula (B), m is 0, q is 1, and each R is ¹¹And R¹²Is H and X⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H. In another aspect of formula (B), m is 0, q is 1, at least one R¹¹And R¹²Is unsubstituted C₁-C₈Alkyl radical, X⁷、X⁸And X¹⁰Are all CR⁴(wherein R is⁴Is H) and X⁹Is CR⁴(wherein R is⁴Is unsubstituted C₁-C₈Alkyl groups). In another aspect of formula (B), m is 0, q is 1, R¹¹Is H, R¹²Is a compound of formula (I) in the formula (H),X⁷、X⁸and X¹⁰Are all CR⁴(wherein R is⁴Is H) and X⁹Is CR⁴(wherein R is⁴Is unsubstituted C₁-C₈Alkyl groups). In any of the variations of formula (B) detailed herein, where applicable, in one aspect Q is a substituted or unsubstituted aryl, such as phenyl or mono-or di-halophenyl or a substituted or unsubstituted heteroaryl, such as pyridyl or methyl-substituted pyridyl. When Q is pyridyl, it may be substituted with R^8eAnd R^8fIs attached at any available ring position (e.g., Q can be 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.). In one aspect, a substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridyl) is substituted with 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C ₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, and aminocarbonylamino moieties. In one such variation, Q is phenyl or pyridyl, which is substituted with at least one substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or halo (e.g., fluoro). Q may also be substituted with a single moiety, for example 4-fluorophenyl or 6-methyl-3-pyridyl.

In one embodiment, the compound is a compound of formula (II) or (B) as detailed herein or any variation thereof, wherein p is 1 and each R is^2b、R^3aAnd R^3bIndependently H, halogen or substituted or unsubstituted C₁-C₈Alkyl, or R^3aAnd R^3bTogether with the carbon to which they are attached form a cycloalkyl moiety or a carbonyl moiety, each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group. In another embodimentIn one embodiment, the compound is a compound of formula (II) or (B) as detailed herein or any variation thereof, wherein p is 1 and each R is^2b、R^3aAnd R^3bIndependently H, halogen or substituted or unsubstituted C₁-C₈Alkyl radical, each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C ₁-C₈An alkyl group.

In one embodiment, the compound is a compound of formula (II) or (B) as detailed herein or any variation thereof, wherein p is 2 and each R is^2b、R^3aAnd R^3bIndependently H, halogen or substituted or unsubstituted C₁-C₈Alkyl, or R^3aAnd R^3bTogether with the carbon to which they are attached form a cycloalkyl moiety or a carbonyl moiety, each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group. In another embodiment, the compound is a compound of formula (II) or (B) as detailed herein or any variation thereof, wherein p is 2 and each R is^2b、R^3aAnd R^3bIndependently H, halogen or substituted or unsubstituted C₁-C₈Alkyl radical, each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group.

In one variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; x⁷、X⁸And X¹⁰Are all CR⁴(wherein R is⁴Is H); x⁹Is CR⁴(wherein R is⁴Is H, halogen or substituted or unsubstituted C₁-C₈Alkyl groups). In one such variation, the compound is further defined by the following features: q is substituted aryl or substituted heteroaryl, R^8c、R^8d、R^8eAnd R^8fAre all H. In another such variation, Q is substituted phenyl or substituted pyridyl. When Q is pyridyl, it may be substituted with R ^8eAnd R^8fAt any available ring position(e.g., Q can be 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.). In one aspect, a substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridyl) is substituted with 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, and aminocarbonylamino moieties. In one such variation, Q is phenyl or pyridyl, which is substituted or unsubstituted with at least one substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or halo (e.g., fluoro). Q may also be substituted with a single moiety, for example 4-fluorophenyl or 6-methyl-3-pyridyl. In a particular variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^8c、R^8d、R^8eAnd R^8fAre all H; x⁷、X⁸And X¹⁰Are all CR⁴(wherein R is ⁴Is H); x⁹Is CR⁴(wherein R is⁴H, Cl or Me); q is phenyl or pyridyl, substituted or unsubstituted C₁-C₈Alkyl or halogen substitution.

In another variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^8c、R^8d、R^8eAnd R^8fAre all H; x⁹Is CR⁴(wherein R is⁴Is Cl); r^3aAnd R^3bAre all H or substituted or unsubstituted C₁-C₈An alkyl group. In one such variation, the compound is further defined by the following features: q is substituted aryl or substituted heteroaryl. When Q is substituted aryl or substituted heteroaryl, it may be as defined in the preceding paragraph, including phenyl or pyridyl, which is substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or halo (e.g., fluoro). In one such variation, R^3aAnd R^3bOne of which is substituted or unsubstituted C₁-C₈Alkyl (e.g. C)₁-C₄Alkyl, such as methyl or ethyl), and the other is H. In another such variation, R^3aAnd R^3bAre all H. In one aspect, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^8c、R^8d、R^8eAnd R^8fAre all H; x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; r^3aAnd R^3bAre all H or unsubstituted C₁-C₈An alkyl group.

In another variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r ^8cAnd R^8dAre all H; r^8eAnd R^8fOne is OH, C₁-C₈Alkyl radical, R^8eAnd R^8fAnother one is H, C₁-C₈Alkyl, or R^8eAnd R^8fTogether form a cyclopropyl moiety, a methylene moiety, or a carbonyl moiety. In a particular variant, said C₁-C₈The alkyl group is a methyl group. In another variation, R^2b、R^3a、R^3b、R^10aAnd R^10bAre all H.

In another variant of formula (II), q is 0; m and n are both 1; r^8cAnd R^8dAre all H; r^8eAnd R^8fTogether form a carbonyl moiety; q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted amino. In a particular variation, Q is phenyl. In another particular variant, Q is piperazin-4-yl, piperidin-4-yl, cyclohexylamino, morpholino or dimethylamino.

In another variant of the formula (II)In the scheme, q is 0; m and n are both 1; r^8cAnd R^8dTogether form a carbonyl moiety; r^8eAnd R^8fAre all H; q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted amino. In a particular variation, Q is phenyl. In another particular variant, Q is piperazin-4-yl, piperidin-4-yl, cyclohexylamino, morpholino or dimethylamino.

In another variation, there is provided a compound of formula (II), wherein q is 0; m and n are both 1; r^3aAnd R^3bAre all H. In one variation, the compound is further defined by one or more of (i) - (iv): (i) x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine), C₁-C₈Perhaloalkyl (e.g. CF)₃) Or unsubstituted C₁-C₈Alkyl (e.g., methyl); (ii) r^8cAnd R^8dTogether form a carbonyl moiety; (iii) r^8eAnd R^8fOne is hydroxy and the other is H or methyl; (iv) q is a substituted or unsubstituted phenyl. In one such variant, (i) and (ii) apply. In another variant, both (i) and (ii) and (iv) are applied. In another variant, both (i) and (iii) are applicable. In another variant, the terms (i), (iii) and (iv) apply.

In another variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^3aAnd R^3bAre both H and Q includes a phenyl or pyridyl moiety. In one such variation, Q is phenyl or substituted phenyl. In another such variation, Q is phenyl, which is substituted with one halogen or one substituted or unsubstituted alkyl moiety. The phenyl group may be substituted with a halogen moiety (e.g., fluoro), or may be substituted with a substituted or unsubstituted alkyl moiety (e.g., C) ₁-C₄Alkyl, such as methyl). For example, in one variation, Q may be benzeneA group of 2-fluorophenyl, 4-fluorophenyl, 2-methylphenyl or 4-methylphenyl. In another variation, Q is a disubstituted phenyl, wherein the phenyl is substituted with at least two moieties selected from the group consisting of halogen and alkoxy. For example, in this variation, Q can be 3, 4-difluorophenyl, 3, 4-dichlorophenyl, 3-fluoro-4-methoxyphenyl. In another variation, Q is a substituted pyridyl moiety, such as 6-methyl-3-pyridyl. In a particular variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^3aAnd R^3bAre both H and Q is phenyl, phenyl substituted with one halogen moiety or one alkyl moiety or substituted pyridyl. In a more particular variant, the compounds of any of these variants are further defined by the following features: r^8cAnd R^8dWith R^8eAnd R^8fForm a bond together with R not forming a bond together^8c、R^8d、R^8eAnd R^8fIs H or methyl (thus forming an alkene moiety). In a particular such variant, R^8cAnd R^8dAnd R^8eAnd R^8fForm a bond together with R not forming a bond together ^8c、R^8d、R^8eAnd R^8fIs H or methyl. In one aspect, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^3aAnd R^3bAre all H; r^8cAnd R^8dOne and R^8eAnd R^8fOne of which together forms a bond, not all of which form a bond^8cOr R^8dIs H, R not together forming a bond^8eOr R^8fIs methyl. In another such variation, the compound is a compound of formula (II) wherein q is 0; m and n are both 1; r^3aAnd R^3bAre all H; q comprises a phenyl or pyridyl moiety; r^8cAnd R^8dOne and R^8eAnd R^8fOne of which together forms a bond, not all of which form a bond^8cOr R^8dIs H, R not together forming a bond^8eOr R^8fIs methyl.

In another variation, theThe compound is a compound of formula (II), wherein q is 0, m and n are both 1, R^8cAnd R^8dTogether form a carbonyl group. In one such variation, the compound is defined by any one or more of (i) - (iv): (i) r^8eAnd R^8fAre all H; (ii) q is substituted phenyl; (iii) x⁹Is CR⁴Wherein R is⁴Is substituted or unsubstituted C₁-C₈Alkyl or halogen; (iv) r^3aAnd R^3bOne of which is substituted or unsubstituted C₁-C₈Alkyl, phenyl or H, the other being H. Where more than one of (i) - (iv) applies, they may be combined in any manner, e.g., (i) and (ii); (i) and (iv); (ii) and (iii) and (iv), (i), (ii), (iii) and (iv), and the like. In one variation, Q is phenyl substituted with halo, such as 2-fluorophenyl and 2-chlorophenyl. In one variation, X ⁹Is CR⁴Wherein R is⁴Is methyl or chlorine. In a particular variation, the compound is a compound of formula (II) wherein q is 0, m and n are both 1, R^8cAnd R^8dTogether form a carbonyl group; x⁹Is CR⁴Wherein R is⁴Is methyl or chlorine; q is substituted phenyl.

In another variation, the compound is a compound of formula (II) wherein q is 0, m and n are both 1, R^8eAnd R^8fOne is a hydroxyl group. In one such variation, the compound is defined by any one or more of (i) - (vi): (i) r^8eAnd R^8fOne of R being hydroxy, not being hydroxy^8eOr R^8fIs methyl or H; (ii) x⁹Is CR⁴Wherein R is⁴Is substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or halogen (e.g., chlorine); (iii) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (iv) r^2bIs H; (v) r^10aAnd R^10bAre all H; (vi) q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl. In one such variant, there applies (vi) Q is unsubstituted phenyl or is halogen-substituted or unsubstitutedSubstituted C₁-C₈Alkyl-substituted phenyl. When more than one of (i) - (vi) applies, they may be combined in any manner and/or value. For example, in one variant, all of (i) - (vi) apply, and in another variant, 1 or 2 or 3 of (i) - (iv) apply. In one variant, the process applies (ii), X ⁹Is CR⁴Wherein R is⁴Is methyl or chlorine. In another variant, both (ii) and (vi) apply, in another particular aspect, X⁹Is CR⁴Wherein R is⁴Is methyl or chloro and Q is phenyl or 2-or 4-substituted phenyl, wherein the substituents are methyl or fluoro. In a particular variation, the compound is a compound of formula (II) wherein q is 0, m and n are both 1, R^8eAnd R^8fOne is hydroxy and the other is H or methyl, Q is phenyl or phenyl substituted with a halogen or substituted or unsubstituted alkyl moiety.

In another variation, the compound is a compound of formula (II) wherein m and n are both 1 and Q is 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 may be located at any available phenyl ring position. For example, a mono (singly) -or mono-substituted phenyl group may be substituted in the ortho, meta or para positions of the phenyl group. Any useful substitution pattern of the phenyl ring is suitable for di-or tri-substituted phenyl groups (e.g., in ortho-and para-positions; in two ortho-positions; in two meta-positions; in meta-and para-positions; in ortho-, meta-and para-positions; in two ortho-and meta-positions; or in two meta-and para-or ortho-positions). In one aspect, Q is mono-substituted phenyl, wherein the substituents are halogen or substituted or unsubstituted alkyl. In another aspect, Q is di-substituted phenyl, wherein both substituents are halogen. In another aspect, Q is di-substituted phenyl, wherein one substituent is halogen and the other substituent is alkoxy. In one variation Q is phenyl substituted with 1-5 groups, wherein each substituent is independently halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted Or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, or aminocarbonylamino moieties. In another variation, Q is phenyl substituted with at least one of the following groups: substituted or unsubstituted alkyl (e.g., methyl), alkoxy (e.g., methoxy), or halogen (e.g., chloro or fluoro). In another variation, Q is phenyl substituted with at least two halogens, which may be the same or different. In another such variation, Q is phenyl substituted with one halogen and one alkoxy. In one variation Q is 2-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 2, 4-dichlorophenyl, 3, 4-difluorophenyl, 3, 4-dichlorophenyl, or 3-fluoro-4-methoxyphenyl. In another aspect, the compound is a variation of the foregoing, wherein the compound is defined by any one or more of (i) - (v): (i) x ⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (ii) r^8eAnd R^8fOne is hydroxy and the other is H or methyl; (iii) r^8cAnd R^8dOne and R^8eAnd R^8fOne of which together form a bond and R which do not together form a bond^8cOr R^8dIs H, R not together forming a bond^8eOr R^8fIs substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl); (iv) q is 0; and (v) R^3aAnd R^3bIndependently H, methyl, ethyl or phenyl. When more than one of (i) - (v) applies, they may be combined in any manner and/or numerical value, provided that conditions (ii) and (iii) are not combined. For example, in one variation, all of (i) - (ii), (iv) and (v) apply, and in another variation, any 1 or 2 or 3 or 4 or 5 of (i) - (v) apply, provided that (ii) and (iii) are not combined.

In another variationWherein Q is substituted 3-pyridyl (e.g., 6-methyl-3-pyridyl); m and n are both 1 and R^8c、R^8d、R^8e、R^8fAre all H; r^10aAnd R^10bAre all H. In one such variation, the compound is defined by any one or more of the following conditions: (i) x⁹Is CR⁴Wherein R is⁴Is substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl) or halogen (e.g., chlorine); (ii) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is ⁴Is H; (iii) r^3aAnd R^3bAre all H; and (iv) q is 0.

In another such variation, the compound is a compound of formula (IIh), which is defined by any one or more of (i) - (viii), provided that only one of (ii), (iii), and (iv) applies: (i) q is 0; (ii) r^8cAnd R^8dAre all H and R^8eAnd R^8fIndependently is H, hydroxy or methyl; (iii) r^8cAnd R^8eTogether form a bond and R^8dAnd R^8fTogether form a bond, thereby enabling the carrying of such R⁸Triple bonds are formed between the carbons of the group; (iv) r^8cAnd R^8dOne and R^8eAnd R^8fOne of which together form a bond and R which do not together form a bond^8cOr R^8dIs H, R not together forming a bond^8eOr R^8fIs H or methyl; (v) x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine) or substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl); (vi) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (vii) r^2bIs H; and (viii) R^10aAnd R^10bAre all H. When more than one of (i) - (viii) applies, they may be combined in any manner and/or value, provided that only one of (ii), (iii) and (iv) applies. In a particular variation, the compound is a compound of formula (IIh) or a variation thereof, wherein any one or more of (i) - (viii) applies (provided that only (ii), (iii) and (viii) apply (iv) One of them), wherein R⁹Is halogen, perhaloalkyl, alkoxy or substituted or unsubstituted C₁-C₈Alkyl and s is an integer from 1 to 2.

In one such variation, the compound is a compound of formula (IIg), which is further defined by any one or more of (i) - (vi): (i) q is 0; (ii) m and q are both 1 and R^8c、R^8d、R^8eAnd R^8fAre all H; (iii) x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine) or substituted or unsubstituted C₁-C₈Alkyl (e.g., methyl); (iv) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (v) r^2bIs H; and (vi) R^10aAnd R^10bAre all H. When more than one of (i) - (vi) applies, they may be combined in any manner and/or value. The pyridyl ring can be attached to the parent structure at any available position, e.g., the pyridyl group can be 2-pyridyl, 3-pyridyl, or 4-pyridyl. In addition, when t is greater than 0, R⁹Can be attached to the pyridine ring at any ring position. In one example, t is 1 and pyridyl is 3-pyridyl, wherein R is⁹The moieties are attached at any available ring position. In a particular variation, the compound is a compound of formula (IIg) or a variation thereof, including where any one or more of (i) - (vi) apply, wherein R⁹Is substituted or unsubstituted C ₁-C₈Alkyl and t is an integer of 1 to 2. In a particular such variant, R⁹Is methyl and t is 1, for example to form 6-methyl-3-pyridyl.

In one variation, the compound is any one of formulas (A), (A1) - (A4), (B), and (B1) - (B4), wherein q is 0,represents the E double bond configuration, R¹¹Is H and R¹²Is C₁-C₈An alkyl group. In one variation, the compound is any of formulas (A), (A1) - (A4), (B), and (B1) - (B4)One, wherein q is 0,represents the Z double bond configuration, R¹¹Is H and R¹²Is C₁-C₈An alkyl group.

In one variation, the compound is a compound of formula (B), wherein Q is phenyl or substituted phenyl. When Q is substituted phenyl, in one aspect it is substituted with 1 to 5 substituents. When Q is a substituted phenyl, the substituent may be located at any available phenyl ring position. For example, a mono (singly) -or mono-substituted phenyl group may be substituted in the ortho, meta or para positions of the phenyl group. Any useful substitution pattern of the phenyl ring is suitable for di-or tri-substituted phenyl groups (e.g., in ortho-and para-positions; in two ortho-positions; in two meta-positions; in meta-and para-positions; in ortho-, meta-and para-positions; in two ortho-and meta-positions; or in two meta-and para-or ortho-positions). In one aspect, Q is mono-substituted phenyl, wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl, and 4-fluorophenyl). In another aspect, Q is di-substituted phenyl, wherein two substituents are halo (e.g., 3, 4-difluorophenyl, 3, 4-dichlorophenyl, and 2, 4-dichlorophenyl). In another aspect, Q is 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 another aspect, the compound is a variation of the foregoing, which is further defined by any one or more of (i) - (x), with the proviso 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) r ¹¹Is H; (iii) r¹²Is unsubstituted alkyl (e.g. C)₁-C₈Alkyl groups such as methyl); (iv) r^3aAnd R^3bOne is methyl, ethyl or phenyl and the other is H; (v) r^3aAnd R^3bAre all H; (vi) r¹¹And R¹²Together form a bond, thereby forming an ethynyl moiety; (vii) x⁹Is CR⁴Wherein R is⁴Is unsubstituted alkyl (e.g., methyl) or halogen (e.g., chlorine); (viii) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (ix) r^2bIs H; (x) R^10aAnd R^10bAre all H. When more than one of (i) - (x) applies, they may be combined in any manner and/or numerical value, provided that conditions (iv) and (v) are not combined, conditions (ii) and (vi) are not combined, and conditions (iii) and (vi) are not combined. In a particular variant, the condition (iii) (R) applies¹²Unsubstituted alkyl) and the double bond in compound (B) is in the "E" configuration. In another variation, condition (iii) (R) applies¹²Unsubstituted alkyl) and the double bond in compound (B) is in the "Z" configuration.

In a particular variation, the compound is a compound of formula (B), wherein Q is unsubstituted phenyl and R is¹¹And R¹²Are all H. In a more specific variation, the compound is further defined by each of conditions (i) - (vi): (i) q and m are both 0; (ii) r ^3aAnd R^3bAre all H; (iii) x⁹Is CR⁴Wherein R is⁴Is unsubstituted alkyl (e.g., methyl) or halogen (e.g., chlorine); (iv) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (v) r^2bIs H; and (vi) R^10aAnd R^10bAre all H.

In a particular variation, the compound is a compound of formula (B), wherein Q is substituted phenyl and R is¹²Is methyl. In a more specific variation, the compound is further defined by each of conditions (i), (ii), (vii) - (x): (i) q and m are both 0; (ii) r¹¹Is H; (vii) x⁹Is CR⁴Wherein R is⁴Is unsubstituted alkyl (e.g., methyl) or halogen (e.g., chlorine); (viii) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (ix) r^2bIs H; and (x) R^10aAnd R^10bAre all H. In an even more specific variantThe compound is a compound of formula (B), wherein Q is substituted phenyl and R¹²For methyl, each of the conditions (i), (ii), and (vii) - (x) applies and condition (iv) applies: (iv) r^3aAnd R^3bOne is methyl, ethyl or phenyl and the other is H. In another specific variation, the compound is a compound of formula (IIi) wherein Q is substituted phenyl and R is¹²For methyl, each of the conditions (i), (ii), and (vii) - (x) applies and (v) also applies: (v) r ^3aAnd R^3bAre all H.

In one variation, the compound is a compound of formula (B4), whereinRepresents the E double bond configuration, R¹¹Is H and R¹²Is C₁-C₈An alkyl group. In one variation, the compound is a compound of formula (IIi), whereinRepresents the Z double bond configuration, R¹¹Is H and R¹²Is C₁-C₈An alkyl group.

In one variation, the compound is a compound of formula (B4), wherein Q is a substituted phenyl group, such as those described above in formula (B), including but not limited to: mono-substituted phenyl, wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl, and 4-fluorophenyl); di-substituted phenyl, where both substituents are halo (e.g., 3, 4-difluorophenyl, 3, 4-dichlorophenyl, and 2, 4-dichlorophenyl), or when one substituent is halo, the other is alkoxy (e.g., 3-fluoro-4-methoxyphenyl). Compounds of formula (B4) wherein Q is substituted phenyl may be further defined by any one or more of (i) - (vi): (i) r¹¹Is H; (ii) r¹²Is unsubstituted alkyl (e.g. C)₁-C₈Alkyl groups such as methyl); (iii) x⁹Is CR⁴Wherein R is⁴Is halogen (e.g., chlorine) or alkyl (e.g., methyl); (iv) x⁷、X⁸And X¹⁰Are all CR ⁴Wherein R is⁴Is H; (v) r^2bIs H; and (vi) R^10aAnd R^10bAre all H. When more than one of (i) - (vi) applies, they may be combined in any manner and/or value. In one variation, the compound is a compound of formula (B4), wherein Q is substituted phenyl and all conditions (i) - (vi) apply.

In a particular variant of formula (B4), R¹¹Is H and Q is a substituted or unsubstituted aryl or heteroaryl group, e.g., a substituted or unsubstituted phenyl or pyridyl group. In a more specific variant of formula (B4), R¹¹Is H, R¹²Is H or methyl and Q is a substituted or unsubstituted aryl or heteroaryl. Examples of substituted or unsubstituted phenyl or pyridyl Q include, but are not limited to, 3-pyridyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 4-methyl-3-pyridyl, 4-fluorophenyl, and 2-methyl-5-pyrimidinyl.

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., 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-trifluoromethyl-3-pyridyl, and 4-methyl-3-pyridyl.

In another particular variation of (IIf), Q is substituted phenyl. In one aspect, compounds of formula (IIf) wherein Q is substituted phenyl include, but are not limited to: mono-substituted phenyl, wherein the substituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl, 4-chlorophenyl, and 4-fluorophenyl); II-substituted phenyl, wherein both substituents are halogen (e.g. 3, 4-difluorophenyl, 3, 4-dichlorophenyl and 2, 4-dichlorophenyl), or when one substituent is halogen, the other is alkoxy (e.g. 3-fluoro-4-methoxyphenyl). Compounds of formula (IIk) wherein Q is substituted phenyl may be further defined by one or more of (i) - (v): (i) r^3aAnd R^3bOne is methyl, ethyl or phenyl and the other is H; (ii) x ⁹Is CR⁴Wherein R is⁴Is halogen (e.g., chlorine) or alkyl (e.g., methyl); (iii) x⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H; (iv) r^2bIs H; and (v) R^10aAnd R^10bAre all H. Where more than one of (i) - (v) applies, they may be combined in any manner and/or value. In one variation, the compound is a compound of formula (IIf), wherein Q is substituted phenyl and conditions (i) - (v) apply.

Any of the formulae detailed herein in one variation, if applicable, has R^3a、R^3b、R^10a、R^10bIndependently selected from H, hydroxy, alkoxy or substituted or unsubstituted C₁-C₈An alkyl group. It is understood that "if applicable" means that R is said to be R if a structural formula contains such a structure^3a、R^3b、R^10a、R^10bAnd the part is a variant scheme.

All variants associated with formula (II) are equally applicable, if applicable, 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), (A1) - (A4), (B1) - (B4) (III-1), (IV-1), (V-1), (VI-1), (VII-1), G-1, G-2, G-3 and G-4 as if each and all of the variants were specifically and individually listed.

The present invention includes compounds of formula (III) or salts or solvates thereof:

Wherein:

each R^2aAnd R^2bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

R^3bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈CycloalkanesRadical, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R ^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

In one variation, there is provided a compound of formula (III), when conditions (a) and (B) apply:

(A) When p is 1, the conditions (a) to (d) apply: (a) when each X is⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H), X⁹Is CR⁴(it isIn R⁴Is H or methoxy), each q and m is 0, n is 1 and each R is^8eAnd R^8fWhen H, Q is not phenyl, (B) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each q, m and n is 1 and each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not dimethylamino, (c) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not pyrrolidin-1-yl, and (d) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each of q and m is 0, n is 1 and R is^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group;

(B) when p is 2 and each X is⁷-X¹⁰Is CR⁴(wherein R is⁴In the case of H), the conditions (f) to (l) apply: (f) when each of q, m and n is 1 and each R is^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen it is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl which is not substituted azetidinyl, alkoxy, carbonylalkoxy or aminocarbonylalkoxy moiety, (g) when each q, m and n is 1, each R^8a、R^8b、R^8cAnd R^8dIs H and R^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not a substituted amino group of the formula-NHR, wherein R is substituted alkyl, (h) when Q is 0, each of m and n is 1 and R is ^8c、R^8d、R^8eAnd R^8fWhen H, Q is not carboxy and an acylamino group of the formula-C (O) NHR, wherein R is substituted alkyl, (i) Q is 0, each m and n is 1, each R is^8cAnd R^8dIs H and R^8eAnd R^8fWhen they form a carbonyl group together with the carbon to which they are attached, Q is not methoxy(ii) a group and a cyclopentylamino group, (j) when each q and m is 0, n is 1 and each R is^8eAnd R^8fWhen H, Q is not phenyl, methoxy, carboxy, carbonylmethoxy and acylamino [ -C (O) NH-cyclopentyl substituted by cyclopentyl]And (k) when each of q and m is 0, n is 1 and R is^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group; (l) When q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not cyano.

In another variation, one aspect provides formula (III), wherein when each X is⁷-X¹⁰Is CR⁴And each R^2a、R^2b、R^3b、R^10aAnd R^10bWhen both are H, at least one R^8(a-f)Is hydroxyl or alkoxy.

In one variation, there is provided a compound of formula (III), wherein at least one R^8a-R^8fIs a substituted alkyl group, wherein said C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

In certain variations, the compound is a compound of formula (III) wherein p is 1 and at least one X⁷-X¹⁰Is not CH and Q is not phenyl. In another variation, the compound is a compound of formula (III) wherein p is 1 and Q is substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted heterocyclyl, unsubstituted amino, aminoacyl, acyloxy, carboxyl, aminocarbonylalkoxy, or acylamino. In certain variations, the compound is a compound of formula (III) wherein p is 2 and at least one X⁷-X¹⁰Is not CH. In another variation, the compound is a compound of formula (III) wherein p is 2 and Q is substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, unsubstituted heterocyclyl, acyloxy or aminocarbonylalkoxy.

In certain variations, the compound is a compound of formula (III), wherein when p is 1, conditions (a) - (e) apply: (a) when each X is⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H), X⁹Is CR⁴(wherein R is⁴Is H or methoxy), each R is R when each q and m is 0 and n is 1^8eAnd R^8fIs H and Q is not phenyl; (B) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each q, m and n is 1 and each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not dimethylamino; (c) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), q is 0, each of m and n is 1 and R^8c、R^8d、R^8eAnd R^8fWhen H, Q is not pyrrolidin-1-yl; (d) when each X is ⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), each of q and m is 0, n is 1 and R is^8eAnd R^8fQ is not alkoxy when taken together with the carbon to which they are attached to form a carbonyl group; and (e) when each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H) and each of Q, m and n is 0, Q is not carbonylalkoxy. In certain variations, the compound is a compound of formula (III) wherein p is 2 and each X⁷-X¹⁰Is CR⁴(wherein R is⁴In the case of H), the conditions (f) to (k) apply: (f) when each of q, m and n is 1 and each R is^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fWhen it is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl which is not substituted azetidinyl, alkoxy, carbonylalkoxy or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R^8a、R^8b、R^8cAnd R^8dIs H and R^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not a substituted amino group of the formula-NHR, wherein R is substituted alkyl, (h) when Q is 0, each of m and n is 1 and R is^8c、R^8d、R^8eAnd R^8fWhen H, Q is not carboxy and an acylamino group of the formula-C (O) NHR, wherein R is substituted alkyl, (i) Q is 0, each m and n is 1, each R is^8cAnd R^8dIs H and R ^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not methoxy and cyclopentylamino, (j) when each Q and m is 0, n is 1 and each R is^8eAnd R^8fWhen H, Q is not phenyl, methoxy, carboxy, carbonylmethoxy and acylamino [ -C (O) NH-cyclopentyl substituted by cyclopentyl]And (k) when each of q and m is 0, n is 1 and R is^8eAnd R^8fWhen taken together with the carbon to which they are attached to form a carbonyl group, Q is not an alkoxy group.

In certain variations, the compound is a compound of formula (III), wherein each X is⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3b、R^10aAnd R^10bIs H and at least one R^8(a-f)Is hydroxyl or alkoxy.

The invention includes a compound of formula (IV) or a salt or solvate thereof:

wherein:

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

each R⁴Independently H, hydroxy, nitro, cyano, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C ₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxy, carboxyl, carbonylalkoxy, mercapto, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino, or acyl;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈A cycloalkyl group, a,Substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R ^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

R^10bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group; and

In one variation, there is provided a compound of formula (IV) wherein at least one R^8a-R^8fIs a substituted alkyl group, wherein said C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

In certain embodiments, the compound is a compound of formula (IV), wherein p is 1 and each X is⁷-X¹⁰Is CR⁴(wherein R is⁴Is H), R^8(a-f)M, n, Q and Q together form a moiety which is not tert-butoxycarbonyl.

The present invention includes compounds of formula (V) or salts or solvates thereof:

wherein:

R¹is H or substituted or unsubstituted C ₁-C₈An alkyl group;

R^2bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

R^3bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R ^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

each R^10aAnd R^10bIndependently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group; and is

In one variation, there is provided a compound of formula (V), wherein at least one R ^8a-R^8fIs a substituted alkyl radical, wherein C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

In another variation, there is provided a compound of formula (V), wherein X⁷-X¹⁰Is CR⁴Each ofR is^2b、R^3b、R^10aAnd R^10bAre all H and at least one R^8(a-f)Is hydroxyl or alkoxy.

The present invention includes compounds of formula (VI) or salts or solvates thereof:

wherein:

R¹is H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

R^2bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

each R⁴Independently H, hydroxy, nitro, cyano, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈Alkoxy, aryloxy, carboxyl, carbonylalkoxy, mercapto, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted aminoAcylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

Each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy, alkoxy, halogen, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₂-C₈Alkenyl radical, C₁-C₈Perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or geminal R^8(a-f)Together form a substituted or unsubstituted methylene moiety or a compound of the formula-OCH₂CH₂A group of O-, or with geminal R^8(a-f)And the carbon to which they are attached together form a carbonyl or cycloalkyl group, or with vicinal R^8(a-f)And the carbon atoms to which they are attached together form a substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl or substituted or unsubstituted heterocyclyl, or with vicinal R^8(a-f)Together form a bond, with the proviso that when R^8(a-f)And to vicinal R^8(a-f)Twin R when taken together to form a bond^8(a-f)Is not a hydroxyl group;

R^10bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group; and is

In a variantEach R⁴Independently H, halogen or substituted or unsubstituted C₁-C₈An alkyl group.

In one variation, there is provided a compound of formula (VI), wherein at least one R^8a-R^8fIs a substituted alkyl radical, wherein C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

The present invention includes compounds of formula (VII) or salts or solvates thereof:

wherein:

R¹is H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

R^3bis H, halogen or substituted or unsubstituted C₁-C₈An alkyl group;

each X⁷、X⁸、X⁹And X¹⁰Independently is N or CR⁴；

m and q are independently 0 or 1;

n is 1;

p is 1 or 2;

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₃-C₈Cycloalkenyl, substituted or unsubstituted heteroCyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino.

In one variation, there is provided a compound of formula (VII), wherein at least one R^8a-R^8fIs a substituted alkyl radical, wherein C₁-C₈Alkyl is partially substituted with carbonylalkoxy, carboxyl or acylamino.

In another variation, the compound is a compound of formula (VII), wherein each X is⁷-X¹⁰Is CR⁴Each R^2a、R^2b、R^3bAnd R^10bIs H and at least one R^8(a-f)Is hydroxyl or alkoxy.

The present invention also includes any one or more of the compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1):

q, X therein⁷、X⁸、X⁹、X¹⁰、R¹、R^2a、R^2b、R^3a、R^3b、R^10a、R^10b、R^8c、R^8d、R^8e、R^8fAnd p, if present, are as defined in formulas (III), (IV), (V), (VI) and (VII), respectively. For example, Q, X for formula (III-1)⁷、X⁸、X⁹、X¹⁰、R^2a、R^2b、R^3b、R^10a、R^10b、R^8c、R^8d、R^8e、R^8fAnd p is as defined for formula (III).

In one aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein X⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H. In another aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein each X⁷、X⁸And X¹⁰Is CR⁴(wherein R is⁴Is H), X⁹Is CR⁴(wherein R is⁴And as defined for formulas (III), (IV), (V), (VI) and (VII), respectively, Q is a substituted or unsubstituted aryl or heteroaryl group. In another aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein each X ⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine) or alkyl (e.g. CH)₃Ethyl, isopropyl or tert-butyl); r^8cIs OH; r^8dIs H or CH₃(ii) a Each R^8eAnd R^8fIs H and Q is a substituted or unsubstituted aryl or heteroaryl.

In another aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein each X⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine) or alkyl (e.g. CH)₃Ethyl, isopropyl or tert-butyl); r^8cIs OH; r^8dIs H or CH₃(ii) a Each R^8eAnd R^8fIs H and Q is substituted or unsubstituted pyridyl. In a variant of formulae (V-1), (VI-1) and (VII-I), R¹Is H or substituted or unsubstituted C₁-C₈An alkyl group.

In another aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein each X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Are respectively shown as formulas (III), (IV), (V), (VI) and (VII)Defining; q is a substituted or unsubstituted aryl or heteroaryl. In another aspect, the invention includes compounds of formulae (III-1), (IV-1), (V-1), (VI-1), and (VII-1), wherein X⁷As defined in formulae (III), (IV), (V), (VI) and (VII), respectively; each X ⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴Wherein R is⁴Is halogen (e.g. chlorine) or alkyl (e.g. CH)₃Ethyl, isopropyl or tert-butyl); r^8cAnd R^8cIndependently H, OH or CH₃(ii) a Each R^8eAnd R^8fIs H; q is substituted or unsubstituted aryl or heteroaryl, with the proviso that: (i) when X is present⁷When is N, R^8cAnd R^8dIs H; and (ii) when X⁷Is CR⁴(wherein R is⁴Is H), R^8cIs OH and R^8dIs H or CH₃. In one such embodiment, Q is substituted or unsubstituted pyridyl.

It is to be understood that the variations detailed herein that apply to one structural formula are equally applicable to other structural formulas, as if each and every variation were specifically and individually listed, if applicable. Thus, the variations detailed throughout include those provided below, which apply to all structural formulae, if applicable. In application, it will be understood that such variations apply if the specified structural formula allows for the presence of such variations, for example where a particular group is included in the generic structure (generic structure) or where a particular combination of elements (elements) are allowed to be present in the structure.

In one variation, the compound is of any of the foregoing structural formulae, e.g., any of formulae (I) - (VII), (I-1), (Ia) - (Ik), (Ii-1) - (Ii-7), (IIa-IIk), (IIi-1), (III-1) - (VII-1), (A1) - (A4), (B), and (B1) - (B4), wherein, if applicable, R ¹Is H, hydroxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl radicalPerhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, C₁-C₈Perhaloalkoxy, alkoxy, aryloxy, carboxy, sulfanyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, or carbonylalkylenealkoxy. In another variation, the compound is a compound of any of the foregoing structural formulae, wherein R is¹Is substituted or unsubstituted C₁-C₈An alkyl group or an acyl group. In another variation, the compound is a compound of any of the foregoing structural formulae, wherein R is¹Is unsubstituted C₁-C₈An alkyl group. Any variation of the formulae detailed herein may be through R of this paragraph, if applicable¹And (4) partially defining.

In a particular embodiment, the compound is a compound of the structural formulae detailed herein, e.g., any of the compounds of formulas (I) - (VII), (I-1), (Ia) - (Ik), (Ii-1) - (Ii-), (IIa-IIk), (IIi-1), (III-1) - (VII-1), (A1) - (A4), (B), and (B1) - (B4), wherein X is ⁷、X⁸、X⁹And X¹⁰Is CR⁴. In another embodiment, the compound is a compound of the structural formulae detailed herein, for example, formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein at least one X is⁷、X⁸、X⁹And X¹⁰Is N. Another variation provides compounds of the formulae herein, e.g., compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein at least two X' s⁷、X⁸、X⁹And X¹⁰Is N. Another variation provides compounds of the formulae herein, e.g., compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein two X's are⁷、X⁸、X⁹And X¹⁰Is N and two X⁷、X⁸、X⁹And X¹⁰Is CR⁴. The invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein X is⁷、X⁸、X⁹And X¹⁰One is N and X⁷、X⁸、X⁹And X¹⁰Three of them are CR⁴。

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein X is⁷、X⁸、X⁹And X¹⁰Together form an aromatic moiety selected from the following structures:

wherein each R⁴As defined for formula (I) or (A); or in a particular variant, wherein each R⁴Independently of one another, hydroxy, halogen, C ₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈An alkoxy group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a sulfanyl group, a substituted or unsubstituted amino group, an alkylsulfonylamino group, or an acyl group; or in another variation, wherein R⁴Independently of halogen, unsubstituted C₁-C₄Alkyl or C₁-C₄A perhaloalkyl group. In another variation, each R⁴Independently is halogen or unsubstituted C₁-C₈An alkyl group. In one embodiment, the aromatic moiety is substituted with a single R⁴Substituted by radicals which in one variant are halogen or unsubstituted C₁-C₈An alkyl group. At one isIn such a variant, the aforementioned ring comprises (R)⁴)₀A substituent such that the aromatic moiety is unsubstituted and does not contain R⁴A group.

Wherein each R⁴As defined for formula (I); or in a particular variant, wherein each R⁴Independently is alkyl, perhaloalkyl or halogen; or in an even more specific variant wherein each R⁴Independently methyl, trifluoromethyl, chloro or fluoro. In one embodiment, the aromatic moiety is substituted with a single R⁴Substituted by radicals which in one variant are halogen or unsubstituted C₁-C₈An alkyl group. In one such variant, the aforementioned ring comprises (R)⁴)₀A substituent such that the aromatic moiety is unsubstituted and does not contain R⁴A group.

In another variation, the compound is of a structural formula detailed herein, such as compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4), wherein X is⁷、X⁸、X⁹And X¹⁰Together form the following structural formula, wherein R⁴May be as defined in any of the variations above herein:

in one such variation, R⁴Is halogen or unsubstituted C₁-C₈Alkyl radical。

Wherein R is⁴As defined for formula (I), or in a particular variant, wherein R⁴Is hydroxy, halogen, C₁-C₈Perhaloalkyl, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈Perhaloalkoxy, C₁-C₈An alkoxy group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a sulfanyl group, a substituted or unsubstituted amino group, an alkylsulfonylamino group, or an acyl group; or in a particular variant, wherein each R⁴Independently of halogen, unsubstituted C₁-C₄Alkyl or C₁-C₄A perhaloalkyl group. In another variation, R⁴Is halogen or unsubstituted C₁-C₈An alkyl group.

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4), together form an aromatic moiety selected from the following structures:

wherein R is⁴As defined for formula (I) or any particular variation herein, e.g. when each R is R⁴Independently is alkyl or halogen; or in an even more specific variant wherein each R⁴Independently methyl, chlorine, iodine or fluorine.

any of the formulae detailed herein, if applicable, may comprise X in one variation⁷、X⁸、X⁹And X¹⁰Together they form the aromatic moiety detailed herein above. It should be understood that "if applicable" shall mean: in one variation, if a structural formula comprises such a structure, such X⁷、X⁸、X⁹And X¹⁰The groups together form the moieties described herein above. For example, if the specified formula does not contain X therein⁷、X⁸、X⁹And X¹⁰When the groups together form the structure of a pyridyl moiety, then the pyridyl moiety detailed herein above does not apply to this particular structural formula, but the remainder does not apply to the structure in which X is not contained⁷、X⁸、X⁹And X¹⁰The groups together form a structural formula for the structure of the pyridyl moiety.

In another embodiment, the compounds of the invention are of formula (I), wherein X⁷-X¹⁰As defined by formula (I) or as detailed in any of the variations herein, wherein R, if applicable¹Is H, substituted or unsubstituted C ₁-C₈Alkyl, acyl, acyloxyA substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group. In another embodiment, the compounds of the invention are of the formulae detailed herein, for example, compounds of formulas (I), (V) - (VII), (A), and (A1) - (A4), wherein X is⁷-X¹⁰As defined by formula (I) or as detailed in any of the variations herein, wherein R, if applicable¹Is substituted or unsubstituted C₁-C₈An alkyl group, an acyl group, an acyloxy group, a carbonylalkoxy group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group. In a particular variation, the compounds of the invention are of the structural formulae detailed herein, for example, compounds of formulas (I), (V) - (VII), (A), and (A1) - (A4), wherein X is⁷-X¹⁰As defined by formula (I) or as detailed in any of the variations herein, wherein R, if applicable¹Is methyl, ethyl, cyclopropyl, propylate (propylate), trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propionaldehyde, 1-methyl-2-hydroxyethyl, 2-glycolaldehyde, 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 includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), or any variation thereof, detailed herein, wherein R is^2a、R^2b、R^10a、R^10b、R^3a、R^3bAnd p together form a moiety selected from the following structures:

in certain embodiments, there is provided the details detailed hereinA compound of the formula wherein R¹Selected from the following moieties:

the invention also includes compounds detailed herein, such as compounds of formulas (I) - (VII), or any variation thereof detailed herein, wherein q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fTogether form a moiety selected from the following structures:

it is to be understood that in one aspect, any of the formulae detailed herein, where applicable, includes q, m, n, R thereof^8a、R^8b、R^8c、R^8d、R^8eAnd R^8f(where present) they together form part of the detailed description in this paragraph.

In another variation, where applicable, there is provided a compound as detailed herein, wherein q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fTogether form a structural formulaAnd (4) partial. When the above structures are applicable to the structural formulae detailed herein, such as the compounds of formulas (I) - (VII) or any variation thereof, it is understood that q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fThe foregoing sections may be formed together (if applicable) including, but not limited to, the structures in this paragraph. Likewise, any of the formulae detailed herein may, in one variation, include q, if applicable, m、n、R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fTogether (if present) they form part of the detailed description herein above, including but not limited to the structures in this paragraph. It is to be understood that "if applicable" means: in one variation, if a structural formula contains such a structure, the q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fThe groups (if present) together form the moieties described herein above. For example, if a given structural formula does not include q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fCH formed by radicals (if present) together₂CH₂When part of the structure is-CH as detailed herein above₂CH₂Some not applicable to this particular formula, but the remainder not including q, m, n, R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fCH formed by radicals (if present) together₂CH₂Structural formula of the moiety.

The invention also includes compounds detailed herein, such as compounds of formulas (I) - (VII) or any variation thereof detailed herein, wherein R is^8c、R^8dAnd the carbon to which they are attached to R^8e、R^8fAnd carbon or R to which they are attached^8a、R^8bAnd the carbons to which they are attached together form a moiety selected from the following structures, each of which may be optionally substituted, wherein each R⁸Independently of each other is H, hydroxy, C₁-C₈Alkyl radical, C₁-C₈Perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, the compounds of the invention are the inventionStructural formulae detailed herein, such as compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4) or any variation thereof detailed herein before, wherein each R is R⁴Independently is H, halogen, substituted or unsubstituted C₁-C₈Alkyl radical, C₁-C₈A perhaloalkyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted aryl group. In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4) or any variation thereof detailed herein before, wherein each R is R⁴Independently is H or substituted or unsubstituted C₁-C₈An alkyl group. In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4) or any variation thereof detailed herein before, wherein each R is R⁴Is H. The invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (A1) - (A4), (B) and (B1) - (B4) or any variation thereof as detailed herein before, wherein each R is R⁴Independently of each other H, halogen, unsubstituted C ₁-C₄Alkyl radical, C₁-C₄Perhaloalkyl or substituted or unsubstituted aryl. The invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (A1) - (A4), (B) and (B1) - (B4) or any variation thereof as detailed herein before, wherein each R is R₄Independently H, halogen, methyl, perfluoromethyl or cyclopropyl.

The present invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, which may be, but is not limited to, substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furyl, pyrrolyl, or thienyl. In one variation, the compounds of the invention are of the formulae detailed herein, e.g., formulas (I) - (VII), (A1) - (A4),(B) And (B1) - (B4) compounds or any variation thereof as previously detailed herein, wherein Q is substituted or unsubstituted phenyl or pyridyl. In a particular variant, Q is phenyl or pyridyl substituted by at least one methyl group. In another variation, the compounds of the invention are of the structural formulae detailed herein, e.g., compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furyl, pyrrolyl, or thienyl, substituted with at least one substituted or unsubstituted C ₁-C₈Alkyl, halogen or perhaloalkyl are partially substituted. In another variation, a compound of a structural formula detailed herein, e.g., a compound of the invention, is of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof detailed previously herein, wherein Q is substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted heterocyclyl. In another variation, the compounds of the invention are of the structural formulae detailed herein, e.g., compounds of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl, or thiomorpholinyl. In a particular variation, Q is pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl, or thiomorpholinyl, substituted with at least one methyl or halo group. In one variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4) or any variation thereof detailed herein before, wherein Q is unsubstituted C₃-C₈Cycloalkyl or unsubstituted heterocyclyl. In another variation, the compounds of the invention are of the structural formulae detailed herein, e.g., compounds of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl, or pyrrolidinyl moiety. In another variation, the compounds of the invention For structural formulae detailed herein, such as compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl, or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl, or hydroxy group.

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is a moiety selected from the group consisting of the following structures:

wherein each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, or aminocarbonylamino. In one variation, Q is not more than one R⁹And (4) substituting the group. In another variation, Q is substituted with only one R ⁹And (4) substituting the group. In one variation, Q is substituted with two R⁹And (4) substituting the group. In another variation, Q is selected from the aromatic structures detailed, wherein the remainder comprises (R)⁹)₀Moiety such that Q does not contain R⁹Functional groups or of the formula N-R⁹And (4) partial.

wherein each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carbonylalkoxy, sulfanyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl, or aminocarbonylamino. In one variation, Q is not more than one R⁹And (4) substituting the group. In another variation, Q is substituted with only one R⁹And (4) substituting the group. In one variation, Q is substituted with two R ⁹And (4) substituting the group. In another variation, Q is selected from the aromatic structures detailed, wherein the remainder comprises (R)⁹)₀Moiety such that Q does not contain R⁹Functional groups or of the formula N-R⁹And (4) partial.

wherein each R⁹Independently an alkyl, perhaloalkyl or halogen.

wherein R is⁹To ortho-or para-Q, at which position Q and the carrier R^8eAnd R^8fTo the carbon of (c). In one particular variation, Q is of the formula:R⁹to Q in para position, at which Q and R are present^8eAnd R^8fTo the carbon of (c). In another particular variation, Q is of the formula:wherein each R⁹Independently an alkyl, perhaloalkyl or halogen.

Wherein each R⁹Independently is halogen, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈Alkyl, substituted or unsubstituted C₂-C₈Alkenyl, substituted or unsubstituted C₂-C₈Alkynyl, acyl, acyloxy, carboalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulphonylAlkylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is not more than one R⁹And (4) substituting the group. In another variation, Q is substituted with only one R⁹And (4) substituting the group. In one variation, Q is substituted with two R⁹And (4) substituting the group. In another variation, Q is selected from the detailed carbocyclic and heterocyclic structures in which the remainder comprises (R)⁹)₀Moiety such that Q does not contain R⁹Functional groups or of the formula N-R⁹And (4) partial.

In the presence of R⁹In any of the structures or variations of the groups detailed herein, in one variation, each R is⁹Independently is substituted or unsubstituted C₁-C₄Alkyl, halogen, trifluoromethyl or hydroxy. In another variation, each R⁹Independently of one another is methyl, -CH₂OH, isopropyl, halogen, trifluoromethyl or hydroxy.

in another variation, the compound is any of the structural formulas described herein, wherein Q is

in another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is a 6-membered ring heteroaryl or substituted heteroaryl selected from the following structures:

in another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is phenyl or substituted phenyl selected from the following structures:

in another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is a 5-membered ring heteroaryl or substituted heteroaryl selected from the following structures:

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is a 5-membered ring substituted or unsubstituted cycloalkyl or heterocyclyl selected from the following structures:

in another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is a 6-membered ring substituted or unsubstituted cycloalkyl or heterocyclyl selected from the following structures:

in another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is a substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, or acylamino moiety. In a particular variation, Q is an unsubstituted amino group. In another variation, Q is of the formula-N (C)₁-C₈Alkyl radical)₂Substituted amino groups of (e.g. -N (Me) ₂、-N(CH₃)(CH₂CH₃) And (4) partial. In another variation, Q is a cycloalkane of formula-N (H)A group or a substituted cycloalkyl), such as a moiety of the formula:

in another variation, Q is a substituted amino group of the formula-n (h) (aryl or substituted aryl), such as a moiety of the formula:

in a particular variation, Q is amino or substituted amino and R is^8eAnd R^8fTogether forming a carbonyl moiety. In another variation, Q is an acylamino moiety. In another variation, Q is an acylamino moiety and R^8eAnd R^8fAre all hydrogen.

In another variation, Q is of the formula-O-C₁-C₈Alkoxy of alkyl radicals, e.g. -O-CH₂CH₃And (4) partial. In another variation, Q is alkoxy and R^8eAnd R^8fTogether forming a carbonyl moiety. In another variation, Q is a carbonylalkoxy moiety. In another variation, Q is a carbonylalkoxy moiety and R^8eAnd R^8fAre all hydrogen.

In another variation, Q is an acyloxy, aminocarbonylalkoxy, or acylamino moiety. In one variation, Q is an acyloxy, aminocarbonylalkoxy, or acylamino moiety and R is^8eAnd R^8fAre all hydrogen.

In one variation, Q is a moiety selected from the following structures:

The invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is an aminoacyl moiety. In one variation, Q is an aminoacyl wherein at least one R is_aAnd R_bIs H, e.g. when Q is of the formula-NHC (O) R_bThen (c) is performed. 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) -alkylaryl 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-C₃Alkylaryl and-NHC (O) -substituted phenyl. In one particular variation, Q is a moiety of the formula:

in one variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is acyloxy.

In one variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein 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 of the formula-C (O) -O-C ₁-C₆The carbonylalkoxy moiety of an alkyl group. In a particular variant, Q is of formula-C(O)-O-C₂H₅A carbonylalkoxy moiety of (a). In one variation, Q is a carbonylalkoxy moiety selected from the group consisting of: -C (O) -O-C₁-C₁₀Alkyl, -C (O) -O-C₁-C₃Alkylaryl, -C (O) -O-C₁-C₃Substituted alkyl and-C (O) -OH. In another variation, Q is-C (O) -O-C₁-C₆An alkyl group. In one particular variation, Q is a moiety of the formula:

in another variation, the compound is any of the structural formulae described herein, wherein Q is, if applicable, Q is

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, the compounds of formulas (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as previously detailed herein, wherein Q is an aminocarbonylalkoxy moiety. In one variation, Q is of the formula-NHC (O) -O-R_bAminocarbonylalkoxy moiety of (a). In another variation, Q is of the formula-NHC (O) -O-R_bIn which R is_bIs a substituted alkyl group. In a particular variation, Q is of the formula-NH-C (O) -O-CH₂-C(Cl)₃And (4) partial.

The invention also includes compounds of the formulae detailed herein, for example compounds of formulae (I) - (VII), (a1) - (a4), (B), and (B1) - (B4) or any variation thereof as detailed herein before, wherein Q is an acylamino moiety. In one variation, Q is an acylamino group, wherein at least one R is _aAnd R_bIs H, e.g. when Q is of the formula-C (O) N (H) (R)_b) Then (c) is performed. In another variation, Q is an acylamino group, wherein R is_aAnd R_bAre all 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 (C)₁-C₆Alkyl radical)₂and-C (O) N (H) (C)₁-C₃Alkaryl). In one particular variation, Q is a moiety of the formula:

where applicable, any of the formulae described herein may in one variation comprise the moiety Q detailed herein above. It is to be understood that "if applicable" means: if a structural formula contains such a structure, the Q moiety is a variation. For example, if a given structural formula does not contain a structure in which Q is a moiety of phenyl, then the phenyl moiety does not apply to that particular structural formula, but the remainder applies to structural formulas that do not contain a structure in which Q is a moiety of phenyl.

In another variation, the compounds of the invention are of the structural formulae detailed herein, for example, compounds of formulas (I) - (VII), (A1) - (A4), (B), and (B1) - (B4), wherein each X is ⁷、X⁸、X⁹And X¹⁰Independently is N or CH, each R^8a、R^8b、R^8c、R^8d、R^8eAnd R^8fIndependently H or hydroxy, Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to substituted or unsubstituted phenyl or pyridyl. In one variation, when Q is substituted phenyl or pyridyl, it is substituted with at least one methyl group.

In another variation, the compounds of the invention are of the formulae detailed herein, e.g., compounds of formulas (I) - (VII) or hereinAny of the variations thereof as detailed above wherein Q, m, n, Q and R^8a-R^8fTogether form part of the following structure:

in another variation, the compounds of the invention are of the structural formulae detailed herein, e.g., compounds of formulas (I) - (VII) or any suitable variation detailed herein above, wherein Q, m and n, Q, R^8a-R^8f、R¹¹And R¹²Together (if applicable) form part of the following structure:

in another variation, where applicable, any of the formulae described herein may comprise Q, m and n, Q, R in one variation^8a-R^8f、R¹¹And R¹²Together they form a part having the following structure, if applicable:

in one embodiment, the invention also includes compounds of formula G-1:

Wherein:

R⁴is methyl; r^8cIs H, hydroxy or methyl; or R^8cAnd R^8dTogether form a methylene moiety or an oxo moiety; r^8dIs H or methyl; and is

Q is substituted or unsubstituted pyridyl; substituted or unsubstituted phenyl; substituted or unsubstituted phenylthiazole; substituted or unsubstituted piperidinyl; substituted or unsubstituted piperazinyl; a substituted or unsubstituted morpholinyl or substituted amino.

In another embodiment, the invention also includes compounds of formula G-2:

wherein:

R⁴is methyl; r¹³Is CH₂Or oxo; and is

In another embodiment, the invention also includes compounds of formula G-3:

wherein:

R⁴is methyl; r¹³Is CH₂Or oxo; and is

In another embodiment, the invention includes compounds of formula G-2 or G-3 (shown above), wherein R⁴Is methyl; r¹³Is CR_xR_yWherein R is_xAnd R_yIndependently is H or alkyl; q is a substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenylthiazole, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, or substituted amino group.

In another embodiment, the invention also includes compounds of formula G-4:

wherein:

R⁴is methyl; r¹⁴Is H or methyl; and is

In one embodiment, the invention includes compounds of formulae (G-1), (G-2), (G-3), and (G-4), wherein Q is:

examples of compounds of the invention are described in table 1. The compounds described may exist in the form of salts, even if salt forms are not described, and it is to be understood that the invention encompasses all salts and solvates of the compounds described herein, as well as non-salt and non-solvate forms of the compounds, as is well understood by those skilled in the art.

TABLE 1 representative Compounds of the invention

The present invention includes pharmaceutical compositions of any of the compounds detailed herein. Accordingly, the present invention includes pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, a pharmaceutically acceptable salt is an acid addition salt, for example, a salt with an inorganic or organic acid. The pharmaceutical compositions of the present invention may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or for administration by inhalation.

The compounds of the present invention, for example compounds of formula (I), may be used in methods of modulating histamine receptors.

In one aspect, compounds as detailed herein and compositions comprising compounds in pure form are described in detail herein. Compositions, e.g., compositions of substantially pure compounds, comprising the compounds and salts thereof detailed herein are provided. In certain embodiments, a composition comprising a compound or salt thereof detailed herein is in a substantially pure form. Unless otherwise indicated, "substantially pure" refers to a composition that contains no more than 35% impurities, where impurities refer to compounds other than the main compound or salt thereof contained in the composition. In the case of compound 1, a substantially pure composition of compound 1 refers to a composition that includes no more than 35% impurities, wherein the impurities refer to compounds other than compound 1 or a salt thereof. In one embodiment, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises no more than 25% impurities. In another embodiment, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises no more than 20% impurities. In yet another embodiment, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises no more than 10% impurities. In another embodiment, a composition of a substantially pure compound or salt thereof is provided, wherein the composition comprises no more than 5% impurities. In another embodiment, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises no more than 3% impurities. In yet another embodiment, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises no more than 1% impurities. In another embodiment, a composition of a substantially pure compound or salt thereof is provided, wherein the composition comprises no more than 0.5% impurities.

In one embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, a composition comprising a compound in substantially pure form is provided. In another embodiment, the invention encompasses a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another embodiment, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions and methods of administration of the compounds are applicable to any of the compounds or any form thereof detailed herein.

General description of biological experiments

The binding properties of the compounds disclosed herein can be determined for a group of adrenergic G protein-coupled receptors including adrenergic receptors, dopamine receptors, serotonin receptors, histamine receptors, and imidazoline receptors. Binding properties can be assessed by methods known in the art, such as competitive binding assays. In one embodiment, the compound is evaluated by the binding assay detailed herein. The compounds disclosed herein can also be assayed in cell-based assays or in vivo models for further characterization. In one aspect, the compounds disclosed herein are of any of the formulae detailed herein, and also exhibit one or more of the following characteristics: binding of ligands to adrenergic receptors (e.g., alpha) _1D、α_2AAnd alpha_2B) Is/are as followsInhibiting ligand binding to serotonin receptors (e.g., 5-HT)_2A、5-HT_2C、5-HT₆And 5-HT₇) Inhibition of ligand binding to dopamine receptor (e.g., D)_2L) And ligand binding to histamine receptors (e.g., H)₁、H₂And H₃) Inhibition of (3); for serotonin receptors (e.g., 5-HT)_2A、5-HT₆) Agonist/antagonist activity of (a); for dopamine receptor (e.g., D)_2L、D_2S) Agonist/antagonist activity of (a); histamine receptor (e.g., H)₁) Agonist/antagonist activity of (a); activity in a neurosynaptic growth assay; efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction; efficacy in preclinical models of attention/impulse and executive function; efficacy in preclinical models of schizophrenia.

In one embodiment, inhibition of ligand binding to the receptor is determined in the assays described herein. In another embodiment, inhibition of ligand binding to the receptor is determined in assays known in the art. In one embodiment, binding of the ligand to the receptor is inhibited by at least about 80%, as determined in a suitable assay known in the art, such as the assay described herein. In one embodiment, binding of the ligand to the receptor is inhibited by more than any one of about 80%, 85%, 90%, 95%, 100% or from about 85% to about 95% or from about 90% to about 100%, as determined in a suitable assay known in the art, such as the assay described herein. In one embodiment, binding of the ligand to the receptor is inhibited by at least about 80% ± 20%, as determined in assays known in the art.

In one embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors (e.g., a) as detailed herein_1D、a_2A、a_2B、5-HT_2A、5-HT_2C、5-HT₆、5-HT₇、D_2L、H₁、H₂、H₃). In one embodiment of the process of the present invention,the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors (e.g., alpha) as detailed herein_1D、α_2A、α_2B、5-HT_2A、5-HT_2C、5-HT₆、5-HT₇、D₂、H₁、H₂、H₃). In one embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein and are also shown to be directed to one or more of the receptors detailed herein (e.g., serotonin receptor 5-HT)_2ASerotonin receptor 5-HT₆Dopamine receptor D_2LAnd dopamine receptor D_2SHistamine receptor H₁) As determined by the assays described herein. In one embodiment, a compound of the invention inhibits any one of at least about 50%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% of the agonist response of serotonin receptor 5-HT2A, as determined in a suitable assay such as the assay described herein.

In one embodiment, the compounds of the invention exhibit the aforementioned neurotransmitter receptor binding properties, i.e., inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and further stimulate neuronal synaptic growth, e.g., as determined by the assays described herein. In one variation, the compounds of the invention exhibit activity in a neurosynaptic growth assay using primary cultured neurons. In another variation, the compounds of the invention have activity comparable in strength to naturally occurring prototypical neurotrophins such as brain-derived neurotrophic factor (BDNF) and Nerve Growth Factor (NGF). Notably, neuronal synaptic growth plays a key role in new synaptogenesis, which is beneficial for the treatment of neurological diseases. In one embodiment, the neurological disease comprises ADHD. In one embodiment, the growth of the neurosynaptic is observed at a potency of about 1 μ M, as determined in a suitable assay known in the art, such as the assay described herein. In another embodiment, neuronal synaptic growth is observed with a potency of about 500 nM. In yet another embodiment, neuronal synaptic growth is observed with a potency of about 50 nM. In another embodiment, neuronal synaptic growth is observed with a potency of about 5 nM.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also exhibit agonist or antagonist activity against one or more of the receptors detailed herein, and also stimulate neuronal synaptic growth.

In yet another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors detailed herein and/or exhibit the above-described neurotransmitter receptor binding properties and exhibit their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction and in preclinical models of attention/pulsatility and executive function, e.g., exhibit pro-cognitive effects in preclinical models of memory dysfunction. In one variation, the compounds of the invention are effective in preclinical models of memory dysfunction associated with cholinergic hypofunction. Since H1 antagonism can cause sedation, weight gain and cognitive decline, low affinity for this receptor (less than about 80% inhibition of mepyramine binding at 1 μ M in the assays described herein) can be associated with pro-cognitive effects and more desirable side effect profiles. In addition, have enhanced activity as 5-HT ₆The compounds of the invention may have cognitive enhancing effects due to the effect of serotonin through this receptor which may impair memory.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors detailed herein and also show their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, i.e. show pro-cognitive effects in preclinical models of memory dysfunction and in preclinical models of attention/pulsatility and executive function, and further show their agonist or antagonist activity against one or more receptors detailed herein.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also show its efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, i.e. show a pro-cognitive effect in preclinical models of memory dysfunction and in preclinical models of attention/impulse and executive function, and further stimulate neuronal synaptic growth.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors detailed herein and also show their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, i.e., show pro-cognitive effects in preclinical models of memory dysfunction and in preclinical models of attention/impulse and executive function, and further show their agonist or antagonist activity against one or more receptors detailed herein and further stimulate neurosynaptic growth.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein and also have an antipsychotic effect as determined in a preclinical model of schizophrenia, i.e. show its efficacy in a preclinical model of schizophrenia.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also exhibit their efficacy in preclinical models of schizophrenia, and also exhibit their agonist or antagonist activity against one or more of the receptors detailed herein.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also show efficacy in preclinical models of schizophrenia and further stimulate neurosynaptic growth.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein and also show their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention and reducing memory impairment, and in preclinical models of attention/impulse and executive function, as well as in preclinical models of schizophrenia.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also show its efficacy in preclinical models of schizophrenia, and also show its agonist or antagonist activity at one or more receptors as detailed herein, and also show its efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention time and reducing memory impairment, and in preclinical models of attention/impulse and executive function.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also show their efficacy in preclinical models of schizophrenia and further stimulate neurosynaptic growth, and also show their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention time and reducing memory impairment, and in preclinical models of attention/impulse and executive function.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and further exhibit agonist or antagonist activity against one or more of the receptors detailed herein, and further stimulate neurosynaptic growth, and also exhibit efficacy in preclinical models of schizophrenia.

In another embodiment, the compounds of the invention inhibit ligand binding to at least one and up to 11 receptors as detailed herein, and also show their efficacy in preclinical models of schizophrenia, and also show their agonist or antagonist activity against one or more receptors as detailed herein, and further stimulate neuronal synaptic growth, and also show their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention time and reducing memory impairment, and in preclinical models of attention/impulse and executive function.

In another embodiment, the compounds of the invention stimulate the growth of neuronal synapses. In another embodiment, the compounds of the invention show efficacy in preclinical models of schizophrenia and further stimulate neurosynaptic growth. In another embodiment, the compounds of the invention stimulate neurosynaptic growth and further demonstrate their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention time and reducing memory impairment, as well as in preclinical models of attention/impulsivity and executive function. In another embodiment, the compounds of the invention show their efficacy in preclinical models of schizophrenia and further stimulate neurosynaptic growth, as well as their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as prolonging memory retention and reducing memory impairment, and in preclinical models of attention/impulse and executive function.

In one aspect, the compounds of the invention inhibit the binding of ligands to adrenergic receptor alpha_1D、α_2A、α_2BAnd inhibiting ligand binding to serotonin receptor 5-HT₆. In another embodiment, the compounds of the invention inhibit the binding of a ligand to the adrenergic receptor alpha_1D、α_2A、α_2BInhibiting ligand binding to serotonin receptor 5-HT₆And inhibiting ligand binding to one or more of the following receptors: serotonin receptor 5-HT₇、5-HT_2AAnd 5-HT_2C. In another embodiment, the compounds of the invention inhibit the binding of a ligand to the adrenergic receptor alpha_1D、α_2A、α_2BInhibiting ligand binding to serotonin receptor 5-HT₆And inhibiting ligand binding to one or more of the following receptors: serotonin receptor 5-HT₇、5-HT_2AAnd 5-HT_2CAnd also shows weak inhibition of ligand binding to histamine receptor H₁And/or H₂. In one embodiment, it is also shown that strong inhibition of ligand binding to serotonin receptor 5-HT₇The compounds of the present invention are particularly desirable. In another embodiment, the compounds of the invention inhibit the binding of a ligand to the adrenergic receptor alpha_1D、α_2A、α_2BInhibiting ligand binding to serotonin receptor 5-HT₆And also shows weak inhibition of ligand binding to histamine receptor H₁And/or H₂. Weakly inhibiting ligand binding to histamine receptor H ₁Is permissible because agonists of this receptor may be involved in stimulating memory and weight gain. In one embodiment, with histamine receptor H₁Binding was inhibited by less than about 80%. In another embodiment, the ligand binds to histamine receptor H₁Binding is inhibited by less than any of about 75%, 70%, 65%, 60%, 55%, or 50%, as determined in a suitable assay known in the art, such as the assay described herein.

In another embodiment, the compounds of the invention inhibit ligand binding to dopamine receptor D₂. In another embodiment, the compounds of the invention inhibit ligand binding to dopamine receptor D_2L. In another embodiment, the compounds of the invention inhibit ligand binding to dopamine receptor D₂And inhibiting ligand binding to serotonin receptor 5-HT_2A. In another embodiment, the compounds of the invention inhibit ligand binding to dopamine receptor D_2LAnd inhibiting ligand binding to serotonin receptor 5-HT_2A. In another embodiment, the compounds of the present invention inhibit the binding of a ligand to histamine receptor H₁. In certain aspects, the compounds of the invention also exhibit one or more of the following properties: strong inhibitory ligands binding to serotonin receptor 5-HT ₇Potent inhibition of ligand binding to serotonin receptor 5-HT_2APotent inhibition of ligand binding to serotonin receptor 5-HT_2CWeakly inhibiting ligand binding to histamine receptor H₁Weakly inhibiting ligand binding to histamine receptor H₂And to serotonin receptor 5-HT_2AHas antagonistic activity.

In one embodiment, the compounds of the invention exhibit binding properties to any of the receptors detailed herein, and also exhibit agonist/antagonist activity at one or more of the following receptors: serotonin receptor 5-HT_2ASerotonin receptor 5-HT₆Dopamine receptor D_2LDopamine receptor D_2SAnd histamine receptor H₁. In one embodiment, the compounds of the invention exhibit any of the receptor binding properties detailed herein and also stimulate neuronal synaptic growth. In one embodiment, the compounds of the invention exhibit any of the receptor binding properties detailed herein, and also exhibit their efficacy in preclinical models of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as to prolong memory retention and reduce memory impairment, as well as in preclinical models of attention/impulsivity and executive function. In one embodiment, the compounds of the invention exhibit any of the receptor binding properties detailed herein, and also exhibit their efficacy in preclinical models of schizophrenia. In one embodiment, the compounds of the invention exhibit any of the receptor binding properties detailed herein, and also exhibit their activity in any one or more agonist/antagonist assays (e.g., on serotonin receptor 5-HT) _2A、5-HT₆Dopamine receptor D_2LDopamine receptor D_2SAnd histamine receptor H₁Agonist/antagonist efficacy), neuronal synaptic growth, memory dysfunction associated with cholinergic dysfunction/hypofunction, and efficacy in preclinical models of schizophrenia.

In certain aspects, the compounds of the invention inhibit ligand binding to adrenergic receptor a_1D、a_2A、a_2BSerotonin receptor 5-HT₆And dopamine receptor D₂At least about 80%, such as inSuitable assays known in the art such as those determined in the assays described herein. In one embodiment, binding is inhibited by at least about 80%, as determined in a suitable assay, such as the assay described herein. In certain aspects, the compounds of the invention inhibit ligand binding to adrenergic receptor a_1D、a_2A、a_2BSerotonin receptor 5-HT₆And dopamine receptor D_2LAt least about 80% as determined in suitable assays known in the art, such as the assays described herein. In one embodiment, binding is inhibited by at least about 80%, as determined in a suitable assay, such as the assay described herein. In one embodiment, binding of the ligand to the receptor is inhibited by more than any one of about 80%, 85%, 90%, 95%, 100%, or from about 85% to about 95% or from about 90% to about 100%, as determined in a suitable assay known in the art, such as the assay described herein.

In certain aspects, the compounds of the invention exhibit the neurotransmitter receptor binding properties described above, and also exhibit antipsychotic effects. In one variation, the compounds of the present invention have binding properties similar to those of compounds having antipsychotic activity. In another variation, the compounds of the invention are effective in preclinical models of schizophrenia. Furthermore, the compounds of the present invention may possess the cognitive enhancing properties of Dimebon and thus add beneficial pharmacological properties to these antipsychotic molecules. In one embodiment, the compounds of the invention exhibit the neurotransmitter receptor binding properties described above, and also exhibit their pro-cognitive effects in preclinical models of memory dysfunction. In another embodiment, the compounds of the invention exhibit the neurotransmitter receptor binding properties described above and do not exhibit their pro-cognitive effects in preclinical models of memory dysfunction, learning, and memory.

In one embodiment, the compounds of the invention demonstrate a pro-cognitive effect in preclinical models of memory dysfunction, learning, and memory. In another embodiment, the compounds of the present invention have an antipsychotic effect in a preclinical model of schizophrenia. In another embodiment, the compounds of the invention exhibit their pro-cognitive effects in preclinical models of memory dysfunction, learning and memory, and have antipsychotic effects in preclinical models of schizophrenia.

Overview of the method

The compounds described herein are useful for treating, preventing, delaying the onset and/or delaying the development of the following various diseases in an individual such as a human: cognitive diseases, psychiatric diseases, neurotransmitter mediated diseases and/or neurological diseases. In one aspect, the compounds described herein are useful for treating, preventing, delaying the onset and/or delaying the progression of cognitive diseases. In one embodiment, cognitive disorders as used herein include and relate to disorders comprising a cognitive component, such as psychosis (e.g., schizophrenia) comprising a cognitive component (e.g., CIAS). In one embodiment, the cognitive disorder comprises ADHD. In another aspect, the compounds described herein are useful for treating, preventing, delaying the onset and/or delaying the progression of a psychiatric disorder. In one embodiment, a psychiatric disease as used herein includes and relates to a disorder comprising a psychotic component, for example a cognitive disease (e.g. alzheimer's disease) comprising a psychotic component (e.g. alzheimer's disease or dementia psychosis). In one embodiment, a method of improving at least one cognitive and/or psychiatric symptom associated with schizophrenia is provided. In one aspect, methods are provided for improving cognitive ability in an individual who has or is suspected of having CIAS. In a particular aspect, a method of treating schizophrenia is provided, wherein the treatment ameliorates one or more negative symptoms and/or one or more positive symptoms and/or one or more disorganized symptoms of schizophrenia. In yet another aspect, the compounds described herein are useful for treating, preventing, delaying the onset and/or delaying the progression of neurotransmitter-mediated diseases. In one aspect, the neurotransmitter-mediated condition includes ADHD. In one embodiment, neurotransmitter-mediated diseases include spinal cord injury, diabetic neuropathy, allergic diseases (which include food allergies), and diseases involving age-protective activity, such as age-related hair loss (hair loss), age-related weight loss, and age-related visual impairment (cataracts). In another embodiment, neurotransmitter-mediated diseases include spinal cord injury, diabetic neuropathy, fibromyalgia, and allergic diseases (which include food allergies). In yet another embodiment, neurotransmitter-mediated diseases include alzheimer's disease, parkinson's disease, autism, gillander's syndrome, mild cognitive impairment, multiple sclerosis, stroke, and traumatic brain injury. In yet another embodiment, the neurotransmitter-mediated condition includes schizophrenia, anxiety, bipolar disorder, psychosis, depression, and ADHD. In one embodiment, depression as used herein includes and means depression resistant to treatment, depression involving a psychiatric disorder or depression involving a bipolar disorder. In another aspect, the compounds described herein are useful for treating, preventing, delaying the onset and/or delaying the progression of a neurological disease. In one aspect, the compounds described herein may also be useful in the treatment, prevention, delay of onset and/or delay of progression of: cognitive diseases, psychiatric diseases, neurotransmitter-mediated diseases, and/or neurological diseases for which modulation of an aminergic G protein-coupled receptor is believed to be beneficial or beneficial.

The present invention also provides a method for improving cognitive function and/or reducing the effects of psychosis, 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 function and/or reduce the effects of psychosis. In particular embodiments, methods of treating schizophrenia are provided wherein the treatment improves at least one cognitive function, such as improving cognitive function in an individual having or suspected of having CIAS. In other embodiments, methods of treating schizophrenia are provided, wherein the methods reduce the psychotic effects associated with schizophrenia. In one embodiment, a method of treating schizophrenia is provided, wherein the method ameliorates negative symptoms of schizophrenia in an individual in need of such treatment. 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 other embodiments, methods of treating schizophrenia are provided, wherein the methods improve cognitive function and reduce psychotic effects in an individual in need thereof. Also provided are methods of ameliorating one or more negative, positive, and disorganized symptoms of schizophrenia, wherein the methods detail methods of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment. In one embodiment, a method of ameliorating at least one negative symptom of schizophrenia is provided, wherein the method details a method of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment. In another embodiment, methods of ameliorating at least one negative symptom and at least one positive symptom of schizophrenia are provided, wherein the methods detail a method of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment. In another embodiment, there is also provided a method of ameliorating at least one negative symptom and at least one disorganized symptom of schizophrenia, wherein the method details a method of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment. In yet another embodiment, there is also provided a method of ameliorating at least one positive symptom and at least one disorganized symptom of schizophrenia, wherein the method details a method of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment. In yet other embodiments, methods of ameliorating at least one negative symptom, at least one positive symptom, and at least one symptom of a disorder of schizophrenia are provided, wherein the methods detail a method of administering a compound detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such amelioration treatment.

The present invention also provides a method of stimulating neuronal synaptic growth and/or promoting neurogenesis and/or enhancing a neurotrophic effect in an individual, comprising administering to an individual in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, effective to stimulate neuronal synaptic growth and/or promoting neurogenesis and/or enhancing a neurotrophic effect.

The present invention also includes a method of modulating an aminic G protein-coupled receptor comprising administering to a subject in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, effective to modulate the aminic G protein-coupled receptor.

It is to be understood that the methods described herein also include methods of administering compositions comprising the compounds of the present invention.

Methods for treating, preventing, delaying the onset and/or delaying the progression of cognitive, psychiatric, neurotransmitter-mediated and/or neurological disorders

In one aspect, the invention provides a method for treating, preventing, delaying the onset of and/or delaying the progression of a cognitive disease, a psychiatric disease, a neurotransmitter-mediated disease and/or a neurological disease, in which modulation of an aminergic G protein-coupled receptor is believed to be beneficial or beneficial, comprising administering a compound of the invention to a subject in need thereof. In some embodiments, modulating adrenergic receptor alpha _1D、α_2A、α_2BSerotonin receptor 5-HT_2A、5-HT₆、5HT₇Histamine receptor H₁And/or H₂Are expected to be beneficial or beneficial for cognitive, psychiatric, neurotransmitter-mediated and/or neurological disorders. In some embodiments, modulating adrenergic receptor alpha_1D、α_2A、α_2BAnd serotonin receptor 5-HT₆The receptors are expected to be beneficial or beneficial for cognitive, psychiatric, neurotransmitter-mediated and/or neurological disorders. In some embodiments, modulating adrenergic receptor alpha_1D、α_2A、α_2BAnd serotonin receptor 5-HT₆Receptors and receptors that modulate one or more of the following: serotonin 5-HT₇、5-HT_2A、5-HT_2CAnd histamine H₁And H₂Is pre-treatedBeneficial or beneficial to cognitive, psychiatric, neurotransmitter mediated and/or neurological disorders. In certain embodiments, for dopamine receptor D₂Is expected to be beneficial or beneficial for cognitive, psychiatric, neurotransmitter-mediated conditions and/or neurological disorders. In some embodiments, modulation of dopamine receptor D_2LAre expected to be beneficial or beneficial for cognitive, psychiatric, neurotransmitter-mediated and/or neurological disorders. In certain embodiments, dopamine D is modulated _2LReceptors and serotonin receptors 5-HT_2AAre expected to be beneficial or beneficial for cognitive, psychiatric, neurotransmitter-mediated and/or neurological disorders. In some embodiments, the onset of, and/or progression of cognitive, psychiatric, neurotransmitter-mediated, and/or neurological disorders is delayed by the administration of a compound of the invention.

Methods of improving cognitive function and/or reducing psychotic effects

The present invention provides methods for improving cognitive function by administering a compound of the invention to an individual in need thereof. In some embodiments, modulation of adrenergic receptor alpha is required or anticipated_1D、α_2A、α_2BSerotonin receptor 5-HT_2A、5-HT₆、5HT₇Histamine receptor H₁And/or H₂To improve cognitive function. In some embodiments, it is desirable or anticipated that modulation of α is desired_1D、α_2A、α_2BAdrenergic receptor and serotonin 5-HT₆Receptors to improve cognitive function. In some embodiments, it is desirable or anticipated that modulation of α is desired_1D、α_2A、α_2BAdrenergic receptor and serotonin receptor 5-HT₆And receptors that modulate one or more of the following: serotonin receptor 5-HT₇、5-HT_2A、5-HT_2CAnd histamine receptor H₁And H₂To improve cognitive function. In another aspect, the invention includes a method of treating a mammal with a compound of formula (I) A method of administering a compound of the invention to reduce the effects of psychosis to a subject in need thereof. In certain embodiments, dopamine D₂Modulation of the receptor is desirable or required to reduce psychotic effects. In certain embodiments, dopamine D₂Receptor and serotonin 5-HT_2AModulation of the receptor is desirable or required to reduce psychotic effects. In some embodiments, modulation of dopamine D is required or expected to be required_2LReceptors to reduce psychotic effects. In some embodiments, modulation of dopamine D is required or expected to be required_2LReceptor and serotonin 5-HT_2AReceptors to reduce psychotic effects. In some embodiments, a compound of the invention is administered to an individual in need thereof.

Methods of stimulating neuronal synaptic growth, promoting neurogenesis, and/or enhancing neurotrophic effects

In another aspect, the present invention provides a method of stimulating neuronal synaptic growth and/or enhancing neurogenesis and/or enhancing neurotrophic effects comprising administering to an individual in need thereof a compound of the present invention, or a pharmaceutically acceptable salt thereof, under conditions sufficient to stimulate neuronal synaptic growth and/or enhance neurogenesis and/or enhance neurotrophic effects. In some embodiments, a compound of the invention stimulates neuronal synaptic growth at a potency of about 1 μ M, as determined in a suitable assay, such as the assays described herein. In some embodiments, a compound of the invention stimulates the growth of a neurosynaptic with a potency of about 500nM, as determined in a suitable assay, such as the assays described herein. In some embodiments, a compound of the invention stimulates the growth of a neurosynaptic with a potency of about 50nM, as determined in a suitable assay, such as the assays described herein. In some embodiments, a compound of the invention stimulates the growth of a neurosynaptic with a potency of about 5nM, as determined in a suitable assay, such as the assays described herein.

Methods of modulating an aminergic G-protein coupled receptor

The invention also relates to methods for modulating aminergic G eggsA method of white coupled receptor activity comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof under conditions sufficient to modulate the activity of an aminergic G protein-coupled receptor. In some embodiments, the aminergic G protein-coupled receptor is alpha_1D、α_2A、α_2BAdrenergic receptor and serotonin 5-HT₆A receptor. In some embodiments, the aminergic G protein-coupled receptor is alpha_1D、α_2A、α_2BAdrenergic receptor and serotonin 5-HT₆And 5-HT₇A receptor. In some embodiments, the aminergic G protein-coupled receptor is alpha_1D、α_2A、α_2BAdrenergic receptor, serotonin 5-HT₆And one or more of the following receptors: serotonin 5-HT-7, 5-HT_2AAnd 5-HT_2CAnd histamine H₁And H₂A receptor. In some embodiments, the aminergic G protein-coupled receptor is dopamine D₂A receptor. In some embodiments, the aminergic G protein-coupled receptor is dopamine D_2LA receptor. In some embodiments, the aminergic G protein-coupled receptor is dopamine D₂Receptor and serotonin 5-HT_2AA receptor. In some embodiments, the aminergic G protein-coupled receptor is dopamine D_2LReceptor and serotonin 5-HT_2AA receptor. In some embodiments, the aminergic G protein-coupled receptor is histamine H ₁A receptor.

General synthetic method

The compounds of the present invention can be prepared by a number of methods, which are summarized below and more particularly described in the examples below. In the description of the processes below, unless otherwise indicated, when used in the structural formulae, the symbols are understood to represent those groups described above in connection with the formulae (I) - (VII), (a1) - (a4), (B) and (B1) - (B4) or variants thereof.

When it is desired to obtain a particular enantiomer of a compound, it may be obtained from a mixture of the corresponding enantiomers using any suitable conventional method for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be prepared by reaction of a mixture of enantiomers, e.g., a racemate, with a suitable chiral compound. The diastereomers may then be separated by any convenient method, for example by crystallization, and the desired enantiomer recovered. In another resolution method, the racemates can be separated using chiral high performance liquid chromatography. Alternatively, if desired, specific enantiomers may be obtained by using a suitable chiral intermediate in one of the processes.

Chromatography, recrystallization and other conventional separation methods can also be used for intermediate or final products when it is desired to obtain specific isomers of the compounds or to purify the reaction products.

The following abbreviations are used herein: thin Layer Chromatography (TLC); hours (h); minutes (min); seconds (sec); ethanol (EtOH); dimethyl sulfoxide (DMSO); n, N-Dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran (THF); equivalent concentration (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); room Temperature (RT); retention factor (Rf).

General methods of preparation of the compounds of the invention are described in the illustrative methods below. Other compounds of the invention may be prepared by similar methods. For example, scheme Ib illustrates the synthetic methods detailed in scheme Ia, but other compounds of the invention may also be prepared by halogen methods.

The synthesis of the compounds of the invention is shown in general methods 1-19.

Scheme Ia

Schemes 1-6 and general methods 1-18 illustrate synthetic methods for compounds of formulas (II), (IV) and (VI) using the ` Pictet-Spinger ` loop formation conditions.

General procedure 1

The arylhydrazine hydrochloride (1equiv) was mixed with triethylamine (3equiv) and alkyl halide (1equiv) at 25 ℃. The reaction mixture was stirred at room temperature for 1h, then heated at 90 ℃ until completion of the reaction as determined by TLC and LC-MS (about 16 h). The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organic layers were dried (Na) ₂SO₄) And concentrated to give the crude product, which was purified by column chromatography (silica gel, 100-: EtOAc-hexanes gradient elution).

General procedure 2

The arylhydrazine hydrochloride (1equiv) was added to a vigorously stirred solution of tetra-n-butylammonium chloride (0.05equiv) in 50% aqueous sodium hydroxide (1mL/mmol arylhydrazine hydrochloride), followed by the addition of the alkyl halide (1.1 equiv). The mixture was heated at 60 ℃ (oil bath temperature) for 6 h. After cooling to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The whole extract was dried (sodium sulfate) and evaporated in vacuo to give the crude product, which was purified by column chromatography (silica gel, 100-200 mesh, eluent: EtOAc-hexane gradient elution or DCM).

General procedure 3

The hydrazine derivative (1equiv) was converted to its corresponding HCl salt and dissolved in water. The appropriate acetal (1equiv) was added and the mixture was heated at 0-90 ℃ for 3-6 h. The reaction mixture was cooled to RT and saturated NaHCO was added₃An aqueous solution. The product was extracted with EtOAc. The combined organic layers were concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography to afford the product.

General procedure 4

A solution of the appropriate tryptamine derivative (1equiv), formaldehyde (1equiv) in acetonitrile containing 5% TFA (8-10mL/mmol) was stirred at reflux for 15min-2 h. The reaction mixture was cooled to 25 ℃, concentrated under reduced pressure and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography to give the product.

General procedure 5

A mixture of the appropriate carboline derivative with the side chain carboxylate (1equiv) and NaOH (3N, 5 times w/v) in ethanol (5 times w/v) was stirred at 50 ℃ for 3h, then cooled to room temperature and neutralized with conc. The solvent was removed under reduced pressure to give the corresponding crude carboxylic acid. The crude product obtained is purified by silica gel chromatography (100-200 mesh or 230-400 mesh) with a MeOH-DCM gradient, by a neutral oxide column with an EtOAc-hexane gradient and/or by reverse phase chromatography (C-18, 500mm × 50mm, mobile phase a ═ 0.05% aqueous TFA, B ═ 0.05% TFA in acetonitrile, gradient elution: 10% B-80% B30 min., injection volume 5 mL).

General procedure 6

A mixture of the appropriate carboline derivative with the side chain carboxylic acid (1equiv) was stirred with the appropriate alcohol (1equiv), EDCI-HCl (1equiv) and triethylamine (1equiv) in DCM for 12-16 h. The reaction mixture was evaporated in vacuo to give the crude ester, which was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) with MeOH-DCM gradient, by neutral oxide column with EtOAc-hexane gradient and/or by reverse phase chromatography (C-18, 500mm × 50mm, mobile phase a 0.05% aqueous TFA, B0.05% TFA in acetonitrile, gradient elution: 10% B-80% B30 min., injection volume 5 mL).

General procedure 7

A mixture of the appropriate carboline derivative with the side chain carboxylic acid (1equiv) was stirred with the appropriate amine (1equiv), EDCI-HCl (1equiv), and triethylamine (1equiv) in DCM for 12-16 h. The reaction mixture was evaporated in vacuo to give the crude amide, which was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) with MeOH-DCM gradient, by neutral oxide column with EtOAc-hexane gradient and/or by reverse phase chromatography (C-18, 500mm × 50mm, mobile phase a 0.05% aqueous TFA, B0.05% TFA in acetonitrile, gradient elution: 10% B-80% B30 min., injection volume 5 mL).

General procedure 8

The carboline derivative (1equiv), epoxide derivative (4-7.5equiv) and NaH (3equiv) were heated in DMF (3mL/mmol) at 120 ℃ for 16 h. The contents were quenched with MeOH and evaporated to dryness. The crude product obtained was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) eluting with MeOH-DCM gradient, by neutral oxide column with EtOAc-hexane gradient and/or by reverse phase chromatography (C-18, 500mm × 50mm, mobile phase a ═ 0.05% aqueous TFA, B ═ 0.05% TFA in acetonitrile, gradient elution: 10% B-80% B30 min., injection volume 5 mL).

General procedure 9

The appropriate carboline (1equiv) was dissolved in NMP (0.6 mL/mmol). To this solution was added powdered KOH (3.5equiv), and the reaction mixture was stirred at 25 ℃ for 10 min. The appropriate vinylpyridine derivative (1.1equiv) was added and the reaction mixture was heated in a sealed tube at 45 ℃ for 30min. The reaction was monitored by LCMS. After completion of this phase, the reaction mixture was cooled to 25 ℃ and diluted with saturated aqueous NaCl (5 mL). The product was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product obtained was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) eluting with MeOH-DCM gradient, by neutral oxide column with EtOAc-hexane gradient and/or by reverse phase chromatography (C-18, 500mm × 50mm, mobile phase a ═ 0.05% aqueous TFA, B ═ 0.05% TFA in acetonitrile, gradient elution: 10% B-80% B30 min., injection volume 5 mL).

General procedure 10

A4% aqueous solution of sulfuric acid (5mL) was heated at 50 ℃ for more than 30-60 min. The solution was charged with nitrogen while it was heated to remove dissolved air. Hydrazine derivative (1mmol) was added to the heated mixture and the solid was dissolved. The appropriate acetal (1.2mmol) was then added in a flowing manner over 30 minutes and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to RT and 30% aqueous ammonium hydroxide (0.5mL) was added dropwise while maintaining the temperature at 25-30 ℃. The product was extracted with EtOAc. The combined organic layers were concentrated in vacuo to give the crude product, which was passed through silica Purifying the gel by chromatography using EtOAc/ethanol/NH₄OH 7: 3: 1.

General procedure 11

A mixture of the appropriate tryptamine derivative (1.0mmol), formaldehyde (1.0mmol) and TFA (0.15mL) in acetonitrile (3mL) was heated at 25 ℃ for 20 h. The solution was quenched by saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. By flash chromatography (10% CH)₃OH/DCM) the product was isolated as a viscous oil.

Scheme II

General procedure 12

The general procedure for preparing compounds using scheme II is as exemplified for the synthesis of compound a. The appropriate substituted phenylhydrazine is reacted with a 4-carbon protected aminoacetal or aldehyde (U.S. patent application No. 2642438) to produce a substituted 3- (2-aminoethyl) indole. The 3- (pyrrolidin-2-yl) methylindole is then reacted with formaldehyde under standard Pictet splinger reaction conditions [ org. lett. (2003), 5 (1: 43-46] to obtain the N-unsubstituted β -carboline.

General procedure 13

General procedure for the preparation of compounds using scheme III is as exemplified by the synthesis of compound B. The appropriate substituted phenylhydrazine is reacted with a 4-carbon protected aminoacetal or aldehyde (U.S. patent application No. 2642438) to produce a substituted 3- (2-aminoethyl) indole. The 3- (2-aminoethyl) indole was then reacted with formaldehyde under standard Pictet Spingler reaction conditions (U.S. patent application No. 2642438) to yield an N-unsubstituted β -carboline. The beta-carboline is then reacted with aryl and/or heteroaryl styrene oxide (carboline, aryl/heteroaryl oxide, NaH, DMF, 120 ℃) to introduce the side chain labeled Q in synthesis scheme III.

General procedure 14

The general procedure for preparing compounds using scheme IV is as exemplified by the synthesis of compound C: the appropriate substituted phenylhydrazine is reacted with an alkyl halide bearing an ester functional group, followed by reaction with a 4-carbon protected aminoacetal or aldehyde (U.S. patent application No. 2642438) to produce a substituted 3- (2-aminoethyl) indole. The 3- (2-aminoethyl) indole was then reacted with formaldehyde under standard Pictet Spingler reaction conditions (U.S. patent application No. 2642438) to obtain an N-substituted β -carboline. The beta-carboline is then reacted with a base to effect hydrolysis of the ester functionality, resulting in the formation of the free acid. This acid is then reacted with alkyl, aryl and/or heteroaryl primary or secondary amines (carboline derivatives bearing pendant carboxylic acids, appropriate primary or secondary amines, EDCI and triethylamine in DCM for 12-16h) to introduce the group designated R in scheme IV₂And R₃The side chain of (1).

General procedure 15

General procedure for the preparation of compounds using scheme V as exemplified by the synthesis of compound D: the appropriate substituted phenylhydrazine is reacted with an alkyl halide bearing an ester functional group, followed by reaction with a 4-carbon protected aminoacetal or aldehyde (U.S. patent application No. 2642438) to produce a substituted 3- (2-aminoethyl) indole. The 3- (2-aminoethyl) indole can then be reacted with formaldehyde under standard Pictet splinger reaction conditions (U.S. patent application No. 2642438) to obtain an N-substituted β -carboline. The beta-carboline is then treated with a base to effect hydrolysis of the ester functionality, resulting in the formation of the free acid. This acid is then reacted with alkyl, aryl and/or heteroaryl primary alcohols (carboline derivatives bearing pendant carboxylic acids, appropriate primary alcohols, EDCI and triethylamine in DCM for 12-16h) to introduce the group labeled R in scheme V ₂The side chain of (1).

General procedure 16

The appropriate carboline (1equiv, 84mg, 0.34mmol) was dissolved in DMF (15 mL/mmol). To this solution, CuI (10 mol%, 6mg, 0.034mmol), L-proline (20 mol%, 8mg, 0.068mmol), K₃PO₄(2 equiv). The reaction mixture was stirred at room temperature for 10min, followed by addition of 4- (1-bromoprop-1-en-2-yl) -2-fluoro-1-methoxybenzene (1.2 equiv). The reaction mixture was heated at 80 ℃ for 18 h. The solvent was removed under reduced pressure and the residue was diluted with brine and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography.

General procedure 17

Mixing appropriate beta-carboline (1equiv) with CuSO₄·5H₂O (20 mol%), 1, 10-phenanthroline (0.4equiv), K₃PO₄(2equiv) and the appropriate ethylene bromide (1.1equiv) were mixed in toluene (5 mL). Charging nitrogen into the reaction mixtureHeating at 80 deg.C for 16 h. The reaction mixture was filtered through celite and the filter bed was washed with DCM. The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% EtOAc in hexane to afford the product.

General procedure 18

The general procedure for preparing compounds using scheme VI is as exemplified by the synthesis of compound E: the appropriately substituted indole is reacted with a maleimide, followed by reduction with an appropriate reducing agent, to yield a substituted 3- (3-pyrrolidinyl) indole. The 3- (3-pyrrolidinyl) indole may then be reacted with formaldehyde under standard Pictet Spingler reaction conditions (U.S. patent application No. 2642438) to obtain the bicyclic-beta-carboline. The beta-carboline can then be functionalized according to methods similar to those provided in the other general methods described above and in the examples set forth specifically below to incorporate the group designated R in scheme VI ₂The side chain of (1).

General procedure 19

Scheme 7 illustrates the synthesis of the carboline portion of compounds of formula (III), (V) and (VII) using fischer-tropsch indole conditions well known to those skilled in the art. Typically, an appropriately substituted arylhydrazine is condensed with a ketone to form an arylhydrazone, which is heated in dilute acid to complete cyclization to obtain the carboline product. Any isomer can be isolated after this step or the next step, if desired. The carboline can then be substituted at the NH position using the conditions described in the general procedure above. The synthesis of bicyclic ketone intermediates was performed according to basic et al [ j.chem.soc.perkin I (1981), 1346-: 683-689, and Mewshaw et al [ J.Med.chem. (1993), 36: 343-352], wherein the detailed experimental procedures can be incorporated herein by reference.

General procedure for HPLC analysis

(1) Column: phenomenex Gemini C18, 50mm × 4.6 mm; (2) mobile phase A: acetonitrile, B: 10mM ammonium acetate in water; (3) column temperature: 40 ℃; (4) flow rate: 1 mL/min.; (5) gradient elution: maintaining 20% A for 0.3min, 20% A-90% A for 0.3-4.0min, 90% A for 1min, and 5.03-7.00 min.20% A.

The above method may be varied by those skilled in the art. Specific examples of each general method are shown in the following examples.

The following examples are given to illustrate the invention without limiting it.

All references disclosed herein are incorporated by reference in their entirety.

Examples

Example 1: preparation of carboline 1

(A) Preparation of 3- (5-methyl-1H-indol-3-yl) pyrrolidine-2, 5-dione

5-methylindole (10g, 76mmol) and maleimide (7.4g, 76mmol) were heated in 77mL of glacial acetic acid at 90 ℃ for 24 h. The reaction mixture was cooled to room temperature and the acetic acid was evaporated under reduced pressure. The residue was suspended in diethyl ether and filtered to give the solid product (7 g).

(B) Preparation of 5-methyl-3- (pyrrolidin-3-yl) -1H-indole

Lithium aluminum hydride (7.9g, 200mmol) was stirred in anhydrous THF (380mL) at room temperature under nitrogen for 20 min. 3- (5-methyl-1H-indol-3-yl) pyrrolidine-2, 5-dione (9.5g, 41mmol) was added dropwise and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, quenched with aqueous sodium sulfate and filtered. The solid was washed 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: 4.2g, 49.2%.

(C) Preparation of carboline 1

5-methyl-3- (pyrrolidin-3-yl) -1H-indole (8.4g, 42mmol), formaldehyde (5.04g, 168mmol) and TFA (4.78g, 42mmol) were combined in 252mL ethanol and heated to reflux for 3H. Methoxyamine hydrochloride (14.03g, 168mmol) and water (420mL) were added to the reaction mixture and the reaction mixture was heated to reflux for a further 2 h. The solvent was evaporated to a minimum volume. The residue was cooled to 0 ℃, basified with aqueous NaOH 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 solid product obtained was filtered. Yield: 6.4 g.

Example 2: preparation of Compound No. 1

Tetrabutylammonium bromide was dissolved in 50% aqueous sodium hydroxide solution and stirred at room temperature for 10 min. Carboline 1(0.1g, 0.47mmol) was added and the reaction mixture was stirred at room temperature for 10min, followed by the addition of 2- (trifluoromethyl) -5-vinylpyridine. The reaction mixture was stirred at 110 ℃ overnight and the reaction was monitored by TLC, LCMS. After completion, the reaction mixture was cooled to room temperature and the compound was extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford 95mg of the free base. 50mg of the free base was converted to the oxalate salt by treatment with a solution of oxalic acid (1equiv) in THF (30 mg).

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 6.50; purity: 93.08 percent; flow rate: 1.4mL/min.

¹H NMR (DMSO, oxalate) (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), 2.35-2.20(m, 5H), 2.10-1.90(m, 2H).

Example 3: preparation of Compound No. 2

Sodium hydride (33mg, 1.4mmol) was dissolved in dimethylformamide (5mL) and stirred for 10 min. Carboline 1(0.1g, 0.47mmol) was added thereto, and the reaction mixture was stirred at room temperature for 10min, followed by addition of 2- (4-fluorophenyl) -2-methyloxirane. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS. After the reaction was complete, the mixture was quenched by the addition of ice water. The product was extracted twice in EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by reverse phase chromatography to afford 100mg of the title compound, which was converted to the TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 6.15; purity: 98.60 percent; flow rate: 1.4mL/min.

¹H NMR (DMSO, TFA salt) (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), 7.0-6.80(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(80mg, 0.21mmol) was dissolved in 5.6mL of a 25% aqueous solution of sulfuric acid and stirred at 90 ℃ for 3 hours. The reaction mixture was cooled to room temperature, basified with aqueous sodium hydroxide and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by reverse phase chromatography. Yield 15mg as TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 9.85; purity: 90.99 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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%) (50mg, 2.1mmol) was dissolved in dimethylformamide (7.5mL) and stirred for 10 min. Carboline 1(150mg, 0.70mmol) was added and the reaction mixture was stirred at room temperature for 10min, followed by the addition of 2-phenyloxirane (120mg, 1.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with ice water and the product was 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 afford 60mg of the pure product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 5.81; purity: 97.11 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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%) (50mg, 2.1mmol) was dissolved in dimethylformamide (7.5mL) and stirred for 10 min. Carboline 1(150mg, 0.70mmol) was added and the reaction mixture was stirred for 10 min. 2-p-tolyloxirane (134mg, 1.0mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture 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 reverse phase chromatography to afford 68mg of the pure product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 6.11; purity: 95.70 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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%) (50mg, 2.1mmol) was dissolved in dimethylformamide (7.5mL) and stirred for 10 min. Carboline 1(150mg, 0.70mmol) was added and the reaction mixture was stirred for 10 min. 2- (3-fluoro-4-methoxyphenyl) oxirane (168mg, 1.0mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS. The reaction mixture 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 reverse phase chromatography to afford 30mg of the pure product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 5.93; purity: 92.15 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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 (27mg, 1.2mmol) was washed with hexane to remove oil and dried under vacuum. This was suspended in THF. To this mixture was added dropwise a solution of carboline 1(100mg, 0.47mmol) in THF at 0 ℃. The reaction mixture was stirred at rt for 0.5 h. To the reaction mixture was added dropwise a solution of 2-chloro-1- (piperidin-1-yl) ethanone (91mg, 0.56mmol) in THF, which was then stirred at room temperature 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 removed by evaporation and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography to give 17mg of pure product, which was stirred with ethanolic HCl to give the product as the hydrochloride salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile, gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 8.05; purity: 93.33 percent; flow rate: 1 mL/min.

¹H NMR(CD₃OD, free base) (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%) (50mg, 2.1mmol) was dissolved in dimethylformamide (7.5mL) and stirred for 10 min. Carboline 1(150mg, 0.70mmol) was added and the reaction mixture was stirred for 10 min. 2- (3, 4-Dimethoxyphenyl) oxirane (181mg, 1.0mmol) was added and stirred at room temperature overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture 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 reverse phase chromatography to afford 40mg of the pure product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 5.52; purity: 98.70 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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

Tetrabutylammonium bromide (7mg, 0.023mmol) was dissolved in 50% aqueous sodium hydroxide solution at room temperature and stirred for 10 min. Carboline 1(0.1g, 0.47mmol) was added to the reaction mixture and stirred at room temperature for 10 min. 3-fluoro-5-vinylpyridine (69mg, 0.56mmol) was added and the reaction mixture was stirred at 100 ℃ overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to room temperature and the compound was extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by reverse phase chromatography to afford 15mg of the product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 5.51; purity: 95.02 percent; flow rate: 1.4 mL/min.

¹H NMR (DMSO, TFA salt) (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(60mg, 0.17mmol) in DCM (2mL) was added triethylamine (0.036mL, 0.26mmol) and stirred for 10 min. Methanesulfonyl chloride (0.016mL, 0.19mmol) was added slowly at 0 deg.C and the mixture was stirred at room temperature 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 give the crude product. The crude product was dissolved in NMP (1.0mL) and KOH powder (48mg, 0.86mmol) was added thereto at room temperature. The mixture was heated at 80 ℃ overnight. The reaction was monitored by LCMS. The minerals were removed by filtration and the crude product was purified by reverse phase chromatography to afford 4mg of the product as a TFA salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 7.08 of; purity: 91.89 percent; flow rate: 1.4 mL/min.

¹H NMR(CD₃OD, TFA salt) (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 carboline 1(0.1g, 0.47mmol) in 50% sodium hydroxide solution (5mL) was added tetrabutylammonium bromide (8mg, 0.024mmol), followed by 2-vinylpyridine (0.062mL, 0.57 mmol). The reaction mixture was stirred at 90 ℃ overnight. After completion of the reaction (monitored by TLC and LCMS), EtOAc was added and the solution was 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 give the crude product, which was purified by column chromatography. The pure product obtained was dissolved in ethanolic HCl and concentrated to obtain 28mg of HCl salt.

Analytical HPLC: YMC ODS A, 4.6X 150mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: 0.05% TFA in acetonitrile; gradient elution: 5% -95% of B8 min, keeping for 1.5min, and 95% -5% of B0.01 min; retention time (min.): 4.32 of; purity: 95.02 percent; flow rate: 1.4 mL/min.

¹H NMR(CD₃OD, HCl salt) (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 (38mg, 0.012mmol) was dissolved in 50% aqueous sodium hydroxide solution (10mL), and the mixture was stirred at room temperature for 10 min. Carboline 1(500mg, 2.4mmol) was added and the reaction mixture was stirred at room temperature for 10min, followed by the addition of 2- (6-methylpyridin-3-yl) ethyl methanesulfonate (608mg, 2.8 mmol). The reaction mixture was stirred at 110 ℃ overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to room temperature and the compound was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase chromatography to give a TFA salt which was converted to the free base to give 55mg of the title compound.

¹H NMR(CDCl₃Oxalate salt) (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 (7.6mL) and sodium hydride (60%) (62mg, 1.55mmol) was stirred at room temperature for 1 h. To this suspension carboline 1(109mg, 0.51mmol) was added and the mixture was stirred for 10 min. To this same suspension was added 2- (3, 4-dichloro-phenyl) -2-methyloxirane (150mg, 0.73mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was quenched successively with 10mL of MeOH. The solvent was evaporated in vacuo and the crude product was purified by column chromatography on silica gel (100-200 mesh) eluting with MeOH in DCM as the solvent system. The pure product was converted to the oxalate salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 9.57, 9.83; purity: 95.38 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 (7.6mL) and sodium hydride (60%) (62mg, 1.55mmol) was stirred at room temperature for 1 h. To the suspension carboline 1(109mg, 0.51mmol) was added and stirred for 10 min. To this same suspension was added 2- (2, 4-dichloro-phenyl-) 2-methyloxirane (150mg, 0.73mmol), which was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction was quenched successively with 10mL of MeOH. The solvent was evaporated in vacuo and the crude product was purified by column chromatography on silica gel (100-200 mesh) eluting with MeOH: DCM as the solvent system. The pure product was converted to the oxalate salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 10.52, 10.78; purity: 92.34 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 (62mg, 1.68mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1(131mg, 0.617mmol) was added and the reaction mixture was stirred at room temperature for 30 min. 2- (3, 4-difluorophenyl) -2-methyloxirane (150mg, 0.881mmol) was then added. 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 was extracted with EtOAc. The combined organic layers were washed with water (3 ×), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOH in DCM as eluent. The pure product was converted to the oxalate salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B in 15min, keeping for 3min, and 90% -10% of B in 1 min; retention time (min.): 8.06, 8.28; purity: 89.35 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 (67.4mg, 1.68mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1(119mg, 0.6mmol) was added and the reaction mixture was stirred at room temperature for 30 min. 2- (4-chlorophenyl) -2-methyloxirane (150mg, 0.8mmol) was then added. 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 was extracted with EtOAc. The combined organic layers were washed with water (3 ×), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOH in DCM as eluent. The pure product was converted to the oxalate salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 9.11, 9.34; purity: 99.85 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 (74mg, 1.85mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1(130.9mg, 0.88mmol) was added thereto, and the reaction mixture was stirred at room temperature for 30 min. 2- (2, 4-difluorophenyl) -2-methyloxirane (150mg, 0.617mmol) was then added. The reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC and NMR. After completion, the reaction was quenched with MeOH and the solvent was evaporated under reduced pressure. Water was added to the residue and the product was extracted with EtOAc. The combined organic layers were washed with water (3 ×), dried over sodium sulfate and concentrated under reduced pressure and purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOH in DCM as eluent. The pure product was converted to the HCl salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 8.87, 9.06; purity: 84.26 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, HCl salt) (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 (674mg, 1.68mmol) was added to dimethylformamide and stirred for 10 min. Carboline 1(119mg, 0.6mmol) was added and the reaction mixture was stirred at room temperature for 30min, followed by addition of 2- (3-chloro-4-fluorophenyl) -2-methyloxirane (150mg, 0.8 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with MeOH, and then the solvent was evaporated. Water was added to the residue and the product was extracted with EtOAc. The combined organic layers were washed with water (3 ×), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOHDCM solution as eluent. The pure product is converted to its oxalate salt.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 10mM ammonium acetate, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 13.65, 13.81; purity: 84.30 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 20 a: preparation of nitrile 19A

Carboline 1(1g, 47mmol) was stirred in benzene (15mL) and toluene (20 mL). To this solution was added acrylonitrile (1mL, 2.25 mmol). The reaction mixture was stirred at 0 ℃ for 10 min. To the ice-cold solution was added 1mL of Triton-B. 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 diethyl ether. The pure product is converted to its oxalate salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 5.49; purity: 98.33 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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 20 b: preparation of thioamides 19B

A solution of nitrile 19A (1.2g, 4.5mmol) in pyridine (60mL) and triethylamine (5mL) was taken with H₂S is saturated for 25 min. After 72 hours at room temperature the reaction mixture was concentrated in vacuo. The reaction mixture was azeotroped with toluene (3 ×). The product was recrystallized from hexane and diethyl ether. The pure product was converted to its HCl salt.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 10mM ammonium acetate, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 9.98 of the total weight of the mixture; purity: 93.53 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, HCl salt) (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 20 c: preparation of Compound No. 19

Thioamide 19B (100mg, 33mmol) was added to 2-bromoacetophenone (72mg, 36mmol), followed by 2mL of EtOH to HCl. The reaction mixture was heated in a sealed tube at 80 ℃ 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 give the crude product, which was purified by column chromatography (100-200 mesh) using 0-8% MeOH: EtOAc as eluent. The pure product was converted to its HCl salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 9.73; purity: 92.78 percent; flow rate: 1 mL/min.

¹H NMR(CD₃OD, HCl salt) (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 (56mg, 1.41mmol) was added to dimethylformamide (7mL) at room temperature and stirred for 10 min. Carboline 1(100mg, 0.47mmol) was added thereto and the reaction mixture was stirred at room temperature for 30 min. 2- (p-tolyl) methyloxirane (100mg, 0.67mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with MeOH, and the solvent was evaporated in vacuo. Water was added to the residue and the product was extracted with EtOAc. The combined organic layers were washed with water (3 ×), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOH in DCM as eluent. The pure product was converted to the oxalate salt.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 10mM ammonium acetate, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 12.85, 13.06; purity: 92.88 percent; flow rate: 1 mL/min.

¹H NMR(CD₃OD, oxalate) (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 (84mg, 60%, 2.1mmol) was suspended in 5mL of dimethylformamide. Carboline 1(212mg, 1mmol) was added thereto at room temperature followed by 2-bromoacetophenone (218mg, 1.1 mmol). The reaction mixture was stirred at rt for 4 h. The reaction was quenched by the 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 chromatography on silica gel (100-200 mesh, eluent: 0-4% MeOH in DCM). The pure product was converted to its HCl salt.

Analytical HPLC: YMC polymer C18, 4.6X 150mm, 6 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B15 min, keeping for 3min, and 90% -10% of B1 min; retention time (min.): 8.15, 8.40; purity: 78.46 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, HCl salt) (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

Primary alcohol compound No. 2(118mg, 3.2mmol) was dissolved in 9.7mL of 25% aqueous sulfuric acid and stirred at 90 ℃ for 2.5 h. The reaction mixture was cooled, basified with aqueous NaOH and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to give 10mg of the target product as the free base. The free base was converted to its oxalate salt by treatment with oxalic acid (1equiv) in THF.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; flow rate: 1 mL/min.; retention time: 10.335 min; HPLC purity: 99.34 percent.

¹H NMR (DMSO, oxalate) (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%) (50mg, 2.1mmol) was dissolved in THF (5mL) and stirred for 10 min. Carboline 1(150mg, 0.7mmol) was added and the reaction mixture was stirred at room temperature for 10 min. 2-chloro-N-cyclohexylacetamide (171mg, 1.06mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS. After completion of the 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 give the pure product (45 mg). The pure product is converted to its oxalate salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile, gradient elution: 10% -90% of B8 min, keeping for 3min, and 90% -10% of B0.5min; retention time (min.): 6.29; purity: 95.37 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Oxalate salt) (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%) (33mg, 1.4mmol) was dissolved in THF (5mL) and stirred for 10min. Carboline 1(100mg, 0.47mmol) was added and the reaction mixture was stirred at room temperature for 10min. Tert-butyl 4- (2-chloroacetyl) piperazine-1-carboxylate (148mg, 0.56mmol) was added and the mixture was stirred at room temperature 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 afford the Boc protected product. Boc deprotection was accomplished with ethanolic HCl (5mL) overnight at room temperature to afford 74mg of the title compound. The pure product was converted to the oxalate salt.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 10mM ammonium acetate, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 4.34; purity: 97.13 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Oxalate salt) (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%) (50mg, 2.1mmol) was dissolved in THF (5mL) and stirred for 10min. Carboline 1(150mg, 0.7mmol) was added and the reaction mixture was stirred at room temperature for 10min. 2-chloro-1- (4-methylpiperidin-1-yl) ethanone (186mg, 1.06mmol) was added and stirred at room temperature 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 give the pure product (50 mg). The pure product was converted to the oxalate salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 9.14 of the total weight of the mixture; purity: 99.19 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Oxalate salt) (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%) (50mg, 2.1mmol) was dissolved in THF (5mL) and stirred for 10min. Carboline 1(150mg, 0.7mmol) was added and the reaction mixture was stirred at room temperature for 10min. 2-chloro-1-morpholinoethanone (173mg, 1.06mmol) was added and stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS. The reaction mixture 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 give the pure product (70 mg). The pure product was converted to the oxalate salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 5min, and 90% -10% of B1 min; retention time (min.): 7.42; purity: 91.26 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Oxalate salt) (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 (113mg, 4.7mmol) was washed with hexane, dried under vacuum, and stirred in THF (5 mL). To the reaction mixture was added dropwise a solution of carboline 1(200mg, 0.94mmol) in THF (3mL) at 0 ℃. The reaction was stirred at 0 ℃ for 30 min. N, N-Dimethylchloroacetamide (148mg, 1.2mmol) in THF (3mL) was added dropwise and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and the product was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was washed with diethyl ether and hexanes to remove colored impurities to give 125mg of the desired product as the free base.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 6.42; purity: 94.21 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Free base) (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(212mg, 1mmol) was dissolved in 2mL NMP, followed by the addition of potassium hydroxide (560mg, 10 mmol). 4-fluoro-2-bromoacetophenone (217mg, 1mmol) was added to the reaction mixture, which was stirred at room temperature overnight. Water was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography on silica gel (100-200 mesh) using 0-4% MeOH in DCM as eluent. The pure product was converted to the TFA salt.

¹H NMR(CD₃OD, TFA salt) (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(212mg, 1mmol) was dissolved in 2mL NMP, followed by the addition of potassium hydroxide (560mg, 10 mmol). To the reaction mixture was added 2-bromo-1- (4-chlorophenyl) -ethanone (233mg, 1mmol), which was stirred at room temperature overnight. Water was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (100-200 mesh) using 0-4% MeOH in DCM as eluent. The pure product was converted to the TFA salt.

¹H NMR(CD₃OD, TFA salt) (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

Tetrabutylammonium bromide (8mg, 0.024mmol) was dissolved in 50% aqueous sodium hydroxide (5mL) and stirred for 10 min. Carboline 1(100mg, 0.47mmol) was added thereto and the reaction mixture was stirred for 10 min. 4-vinyl pyridine (61mg, 0.57mmol) was added to the reaction mixture, which was stirred at 110 ℃ overnight. The reaction mixture was cooled to rt and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography to afford 50mg of the target compound as the free base. The pure product was converted to the TFA salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 6.75; purity: 95.52 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃TFA salt) (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(2.5g, 11mmol) was dissolved in dimethylformamide (25mL) and the reaction mixture was stirred for 5 min. Sodium hydride (1.3g, 33mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere. 2- (4-fluorophenyl) oxirane (2.1g, 15mmol) was added and stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was poured into ice water. The precipitate obtained is filtered, washed with water and crystallized from diethyl ether. The ether layer was concentrated under reduced pressure, and the residue was stirred in hexane and filtered. The pure compound is converted to the oxalate salt.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 7.11; purity: 92.45 percent; flow rate: 1 mL/min.

¹H NMR (DMSO, oxalate) (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(77mg, 0.36mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6mg, 0.0362mmol), L-proline (8mg, 0.072mmol) and potassium phosphate (154mg, 0.724mmol) were added and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -4-chlorobenzene (100mg, 0.434mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 17 mg.

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 9.055 min; HPLC purity: 99.78 percent.

¹H NMR(CDCl₃TFA salt) (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(212mg, 1mmol) was dissolved in DMF. Copper (I) iodide (19mg, 0.1mmol), L-proline (23mg, 0.2mmol) and potassium phosphate (424mg, 2mmol) were added and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -2, 4-dichlorobenzene (318mg, 1.2mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid product 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: 20mg as TFA salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; flow rate: 1 mL/min; retention time: 10.302 min; HPLC purity: 99.39 percent.

¹H NMR(CDCl₃TFA salt) (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(212mg, 1mmol) was dissolved in DMF, copper (I) iodide (19mg, 0.1mmol), L-proline (23mg, 0.2mmol) and potassium phosphate (424mg, 2mmol) were added, and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -2, 4-dichlorobenzene (318mg, 1.2mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid product 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: 17mg as TFA salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile: gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1 mL/min; retention time: 10.826 min; HPLC purity: 95.04 percent.

¹H NMR(CDCl₃TFA salt) (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(212mg, 1mmol) and CuSO₄.5H₂O (50mg, 0.2mmol), 1, 10-phenanthroline (72mg, 0.4mmol) and potassium phosphate (425mg, 2mmol) are dissolved together in a solution of 1- (bromoethynyl) -4-chlorobenzene (237mg, 1.1mmol) in toluene (8-10mL) and charged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (16 h). The product was monitored by LCMS. The reaction mixture was filtered through celite, washed with DCM and dried over sodium sulfate. The combined organic phases were concentrated under reduced pressure and, without workup, purified by column chromatography (silica gel-60-80% EtOAc in hexanes) to afford the product as a brown semi-solid (23 mg).

Analytical HPLC: sunfire C18, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 8.42; purity: 93.30 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃Free base) (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

Acetylene compound No. 35 was stirred in acetonitrile (0.5mL) and water (0.5 mL). TFA (5-6 drops) was added. The reaction mixture was heated at 55 ℃ 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, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 9.75; purity: 98.72 percent; flow rate: 1 mL/min.

¹H NMR(CDCl₃TFA salt) (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(212.29mg, 1mmol) was dissolved in DMF. Copper (I) iodide (19mg, 0.1mmol), L-proline (23mg, 0.2mmol) and potassium phosphate (424mg, 2mmol) were added and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -2-fluorobenzene (260mg, 1.2mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product 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: 14mg as TFA salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1 mL/min; retention time: 10.016 min; HPLC purity: 99.46 percent.

¹H NMR(CDCl₃TFA salt) (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(212.29mg, 1mmol) was dissolved in DMF. Copper (I) iodide (19mg, 0.1mmol), L-proline (23mg, 0.2mmol) and potassium phosphate (424mg, 2mmol) were added and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -2-fluorobenzene (260mg, 1.2mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product 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: 20mg as TFA salt.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1 mL/min; retention time: 10.462 min; HPLC purity: 95.23 percent.

¹H NMR(CDCl₃TFA salt) (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, 1H)，2H)，2.0(s，3H)。

Example 40: preparation of Compound No. 39

Carboline 1(76mg, 0.36mmol) was dissolved in DMF (6 mL). Copper (I) iodide (8mg, 0.036mmol), L-proline (9mg, 0.086mmol) and potassium phosphate (183mg, 0.86mmol) were added and the reaction mixture was stirred at room temperature for 10min. 4- (1-bromoprop-1-en-2-yl) -1, 2-difluorobenzene (100mg, 0.43mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 43 mg.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 10.478 min; HPLC purity: 98.90 percent.

¹H NMR(CD₃OD, oxalate) (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(67mg, 0.31mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6mg, 0.032mmol), L-proline (7mg, 0.063mmol) and potassium phosphate (134mg, 0.63mmol) were added and the reaction mixture was stirred at room temperature for 10min. 4- (1-bromoprop-1-en-2-yl) -1, 2-dichlorobenzene (100mg, 0.378mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 48 mg.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 11.241 min; HPLC purity: 96.35 percent.

¹H NMR (DMSO, oxalate) (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(72mg, 0.34mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6mg, 0.034mmol), L-proline (8mg, 0.068mmol) and potassium phosphate (145mg, 0.68mmol) were added and the reaction mixture was stirred at room temperature for 10min. 4- (1-bromoprop-1-en-2-yl) -2-fluoro-1-methoxybenzene (100mg, 0.34mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 17 mg.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 10.369 min; HPLC purity: 84.98 percent.

¹H NMR(CD₃OD, oxalate) (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(200mg, 0.943mmol) was dissolved in DMF (6 mL). Copper (I) iodide (17mg, 0.089mmol), L-proline (21mg, 0.18mmol) and potassium phosphate (401mg, 1.88mmol) were added and the reaction mixture was stirred at room temperature for 10min. 3- (1-bromoprop-1-en-2-yl) pyridine (224mg, 1.13mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 90 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid obtained was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 80 mg.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 7.223 min; HPLC purity: 98.63 percent.

¹H NMR(CD₃OD, TFA salt) (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(212mg, 1mmol) was mixed with copper sulfate (50mg, 0.2mmol), 1, 10-phenanthroline (72mg, 0.4mmol), potassium phosphate (425mg, 2mmol) and 1- (bromoethynyl) -4-fluorobenzene (220mg, 1.1mmol) in toluene (8-10mL), and the suspension was charged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (16 h). The reaction mixture was cooled to room temperature, filtered through celite, and the filter bed was washed with DCM. The combined organic layers were concentrated and the residue was purified by silica gel chromatography (60-80% EtOAc in hexanes) to afford a brown semi-solid (23 mg). The solid was stirred in acetonitrile and water (1: 1) and TFA (5-6 drops) was added. The solution was stirred at 55 ℃ for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; retention time (min.): 9.46 of; purity: 99.27 percent; flow rate: 1 mL/min.

¹H NMR(CD₃OD, TFA salt) (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(106mg, 0.5mmol) and potassium phosphate (212mg, 1mmol) were dissolved in DMF and the suspension was charged with nitrogen. The suspension was heated at 90 ℃ for 5 min. In a separate round-bottom flask, 4- (1-bromoprop-1-en-2-yl) pyridine (107.83mg, 0.55mmol), L-proline (11.5mg, 0.1mmol) and copper (I) iodide (9.5mg, 0.05mmol) were dissolved in DMF and the suspension was charged with nitrogen and heated at 90 ℃ for 5min, at which time the suspension became a clear solution. The contents of the two reaction flasks were mixed and the reaction mixture was heated at 90 ℃ overnight. The contents were cooled to room temperature and poured into water. The resulting precipitate was filtered, dried and purified by chromatography on silica gel (100-200 mesh, neutralized with aqueous ammonia) using 0-2% MeOH-DCM as eluent. The product was further purified by reverse phase HPLC.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping for 10min, and 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 7.109 min; HPLC purity: 99.05 percent.

¹H NMR(CD₃OD，TFA salts) (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(78mg, 0.36mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7mg, 0.036mmol), L-proline (8mg, 0.073mmol) and potassium phosphate (156mg, 0.734mmol) were added and the reaction mixture was stirred at room temperature for 10min. 1- (1-bromoprop-1-en-2-yl) -4-methoxybenzene (100mg, 0.44mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80 ℃ overnight (longer heating times were required in some cases). DMF was evaporated under reduced pressure, the residue was diluted with water and the desired solid was filtered. The solid product was purified by silica gel chromatography (100-200 mesh). Yield: 18 mg.

Analytical HPLC: YMC ODS AQ, 4.6X 250mm, 5 μm; mobile phase A: 0.05% TFA, mobile phase B: acetonitrile; gradient elution: 10% -90% of B10 min, keeping 10min, 90% -10% of B1 min; flow rate: 1.0 mL/min; retention time: 10.409 min; HPLC purity: 83.30 percent.

¹H NMR (DMSO, oxalate) (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 (1.0g, 4.7mmol) in DMF was added sodium hydride (564mg, 14.1 mmol). After stirring at room temperature under nitrogen for 5min, a solution of 4-oxiranylpyridine (856mg, 7.0mmol) in DMF (5mL) was added to the reaction mixture and stirring was continued at room temperature. The progress of the 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 layers were washed with water (5X 30mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ether-hexane to give the objective compound (1.0 g).

¹H NMR(CDCl₃Free base) (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 (1000mg, 4.17mmol) in DMF (10mL) was added sodium hydride (500mg, 12.498mmol) in portions. After stirring at room temperature for 5min, 4- (oxiran-2-yl) pyridine (630mg, 5.00mmol) was added dropwise to the reaction mixture, which was stirred at room temperature overnight. The reaction mixture was quenched with ice water and the solid product was filtered. The residue was washed with water (2X 10mL), hexane (2X 50mL) and purified by reverse phase HPLC to give 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 (1g, 4.42mmol) in DMF (10mL) under nitrogen was added sodium hydride (530mg, 13.24mmol) in portions. After stirring at 0 ℃ for 10min, 4-oxiranyl-pyridine (1.07g, 8.84mmol) was added dropwise to the reaction mixture at 0 ℃ and stirring continued at room temperature for 12 h. 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 × 50mL), dried over sodium sulfate and concentrated to yield 1.2g of product.

¹H NMR(CD₃OD, formate) (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 the Compounds of the invention to bind to the Histamine receptor

Histamine H₁

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2mM MgCl) was used₂100mM NaCl, 250mM sucrose) in Chinese Hamster Ovary (CHO) cells ₁Receptors (De Backer MD et al biochem. Biophys. Res Comm. (1993), 197 (3): 1601). A compound of the present invention is used in combination with 1.2nM³H]Mepyramine was incubated at 25 ℃ for 180 minutes. Nonspecific binding was assessed in the presence of 1 μ M mepyramine. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Mepyramine. Compounds were screened at a concentration of 1 μ M or less using 1% DMSO as vehicle. Biochemical assay results are shown in table 2 as percent inhibition of specific binding.

Histamine H₂

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant histamine H expressed in Chinese Hamster Ovary (CHO) K1 cells in 50mM phosphate buffer (pH 7.4) was used₂Receptors (Ruat m. proc Natl Acad Sci USA (1990), 87 (5): 1658, 1990). A compound of the present invention is used in combination with 0.1nM¹²⁵I]Aminopotentidine was incubated at 25 ℃ for 120 min. Nonspecific binding was assessed in the presence of 3 μ M thiodine. The receptor protein is filtered and washed, and the filtrate is then counted to determine specific binding[¹²⁵I]Aminopotentidine. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 2 as percent inhibition of specific binding.

Histamine H₃

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 5mM MgCl) was used₂0.04% BSA) human recombinant histamine H expressed in Chinese hamster ovary (CHO-K1) cells₃Receptors (Yanai K et al, Jpn J Pharmacol, (1994), 65 (2): 107; Zhu Y et al, Mol Pharmacol (2001), 59 (3): 434). Combining a compound of the present invention with 3nM [ 2 ]³H]R (-) -alpha-methyl histamine was incubated at 25 ℃ for 90 minutes. Nonspecific binding was evaluated in the presence of 1 μ M R (-) - α -methyl histamine. Filtering the receptor protein, washing, counting the number of filtrates to determine the specific binding³H]R (-) -alpha-methyl histamine. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Example B2: compounds of the invention and imidazolines I₂Determination of receptor binding Capacity

Central imidazoline I₂

To evaluate the activity of the compounds of the invention in radioligand binding assays, rat central imidazoline I from Wistar rat cerebral cortex in modified Tris-HCl buffer (50mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) was used ₂Receptors (Brown, CM. et al, Br.J. Pharmacol (1990), 99: 803). Combining a compound of the present invention with 2nM 2³H]The idazoxan was incubated at 25 ℃ for 30 min. Nonspecific binding was assessed in the presence of 1 μ M idazoxan. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Imidazole is used for treating diabetes. Sieving at 1. mu.M or lessCompounds were selected using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Table 2 binding data (% inhibition)

Example B3: determination of the ability of the compounds of the invention to bind to adrenergic receptors.

Adrenergic alpha_1A

To evaluate the activity of the compounds of the invention in radioligand binding assays, rat adrenergic alpha from the submaxillary gland of Wistar rats in modified Tris-HCl buffer (50mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) was used_1AReceptors (Michel, A.D., et al, Br.J. Pharmacol. (1989), 98: 883). A compound of the present invention is used in combination with 0.25nM³H]Prazosin (Prozosin) was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10 μ M phentolamine. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ] ³H]Prazosin. Compounds of the invention were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Adrenergic alpha_1B

To evaluate the activity of the compounds of the invention in radioligand binding assays, use was made ofRat adrenergic alpha from Wistar rat liver in modified Tris-HCl buffer (50mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA)_1BReceptors (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). A compound of the present invention is used in combination with 0.25nM³H]Prazosin was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10 μ M phentolamine. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Prazosin. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Adrenergic alpha_1D

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant adrenergic alpha expressed in human embryonic kidney (HEK-293) cells in 50mM Tris-HCl buffer (pH 7.4) was used_1DReceptors (Kenny, B.A. et al Br.J.Pharmacol. (1995), 115 (6): 981). A compound of the present invention is used in combination with 0.6nM³H]Prazosin was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10 μ M phentolamine. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Prazosin. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Adrenergic alpha_2A

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 12.5mM MgCl) was used₂2mM EDTA) of insect Sf9 cells_2AReceptors(Uhlen S et al, JPharmacol Exp Ther. (1994), 271: 1558). A compound of the present invention is combined with 1nM [ 2 ] ³H]MK-912 was incubated at 25 ℃ for 60 minutes. MK912 is (2S-trans) -1, 3, 4, 5 ', 6, 6', 7, 12 b-octahydro-1 ', 3' -dimethyl-spiro [ 2H-benzofuro [2, 3-a ]]Quinolizine-2, 4 '(1' H) -pyrimidines]-2 '(3' H) -keto hydrochloride. At 10. mu.M WB-4101(2- (2, 6-dimethoxyphenoxyethyl) aminomethyl-1, 4-benzodiAlkane hydrochloride) was evaluated for non-specific binding. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]MK-912. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Adrenergic alpha_2B

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 12.5mM MgCl) was used₂1mM EDTA, 0.2% BSA) expressed in Chinese hamster ovary (CHO-K1) cells_2BThe receptor (Uhlen S et al Eur J Pharmacol, (1998), 343 (1): 93). A compound of the present invention is combined with 2.5nM ³H]Rauwolfine was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10 μ M prazosin. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Rauvolcine. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Adrenergic alpha_2C

To evaluate the radioactivity of the compounds of the inventionActivity in ligand binding assays Using modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 12.5mM MgCl)₂2mM EDTA) of insect Sf9 cells_2CReceptors (Uhlen S et al, JPharmacol Exp Ther (1994), 271: 1558). A compound of the present invention is combined with 1nM [ 2 ]³H]MK-912 was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10. mu.M WB-4101. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]MK-912. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay. Biochemical assay results for representative compounds are expressed as percent inhibition of specific binding in table 3.

Example B4: determination of the ability of the compounds of the invention to bind to dopamine receptors.

Dopamine D_2L

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant dopamine D expressed in Chinese Hamster Ovary (CHO) cells in modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 1.4mM ascorbic acid, 0.001% BSA, 150mM NaCl) was used_2LReceptors (Grandy, D.K., et al Proc. Natl.Acad.Sci.USA (1989), 86: 9762; Hayes, G.et al mol. Endocrinol. (1992), 6: 920). A compound of the present invention is used in combination with 0.16nM³H]Spiperone was incubated at 25 ℃ for 120 minutes. Nonspecific binding was assessed in the presence of 10 μ M haloperidol. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Spiperone. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 3 as percent inhibition of specific binding.

Table 3 percent inhibition of ligand binding to an aminergic G protein-coupled receptor by compounds of the invention:

example B5: determination of the ability of the compounds of the invention to bind to serotonin receptors.

Serotonin (5-hydroxytryptamine) 5-HT_1A

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 0.1% ascorbic acid, 0.5mM EDTA, 10mM MgSO 2) was used ₄) Chinese hamster ovary (CHO-K1) cells in (A) and (B) human recombinant serotonin (5-hydroxytryptamine) 5-HT_1AReceptors (Martin GR et al Neuropharmacol (1994), 33: 261; May JA, et al J Pharmacol Exp Ther (2003), 306 (1): 301). A compound of the present invention is used in combination with 1.5nM³H]8-OH-DPAT was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10. mu.M of ergoline. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]8-OH-DPAT. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Serotonin (5-hydroxytryptamine) 5-HT_1B

To evaluate the activity of the compounds of the invention in radioligand binding assays, use was made ofSerotonin (5-hydroxytryptamine) 5-HT from the cerebral cortex of rats in modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 154mM NaCl, 10. mu.M pargyline, 30. mu.M isoproterenol)_1BReceptors (Hoyer et al Eur J Pharmaco (1985), 118: 1; Pazos et al Eur J Pharmacol (1985), 106: 531). A compound of the present invention is used in combination with 10pM¹²⁵I]Cyanopindolol (Cyanopindolol) was incubated at 37 ℃ for 90 minutes. Nonspecific binding was assessed in the presence of 10. mu.M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ] ¹²⁵I]Cyano pindolol. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Serotonin (5-hydroxytryptamine) 5-HT_2A

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant serotonin (5-hydroxytryptamine) 5-HT expressed by Chinese hamster ovary (CHO-K1) cells in 50mM Tris-HCl buffer (pH 7.4) was used_2AReceptors (Bonhaus, D.W. et al Br.J.Pharmacol. (1995), 115: 622; Saucier, C. et al Neurochem. (1997), 68: 1998). A compound of the present invention is used in combination with 0.5nM³H]Ketanserin was incubated at 25 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 1 μ M mianserin. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]Ketanserin. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 4 as percent inhibition of specific binding.

Serotonin (5-hydroxytryptamine) 5-HT_2B

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 4mM CaCl) was used ₂0.1% ascorbic acid) human recombinant serotonin (5-hydroxytryptamine) 5-HT expressed by Chinese hamster ovary (CHO-K1) cells_2BReceptors (Bonhaus, D.W., et al, Br.J.Pharmacol, (1995), 115: 622). A compound of the present invention is used in combination with 1.2nM³H]Lysergic acid diethylamide (LSD) was incubated at 37 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 10. mu.M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]LSD. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. Biochemical assay results are expressed as percent inhibition of specific binding.

Serotonin (5-hydroxytryptamine) 5-HT_2C

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant serotonin (5-hydroxytryptamine) 5-HT expressed in Chinese hamster ovary (CHO-K1) cells in modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 0.1% ascorbic acid, 10. mu.M pargyline) was used_2CReceptors (Wolf, w.a. et al, j.s., j.neurohem (1997), 69: 1449). A compound of the present invention is combined with 1nM [ 2 ] ³H]The melarshal was incubated at 25 ℃ for 60 min. Nonspecific binding was assessed in the presence of 1 μ M mianserin. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]And (4) mersult ergot. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 4 as percent inhibition of specific binding.

Serotonin (5-hydroxytryptamine) 5-HT₃

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 1mM EDTA, 5mM MgCl)₂) Human recombinant serotonin (5-hydroxytryptamine) 5-HT expressed in human embryonic kidney (HEK-293) cells of (III)₃Receptors (Miller K et al, Synapase. (1992), 11: 58; Boess F et al, Neuropharmacology. (1997), 36: 637). A compound of the present invention is used in combination with 0.69nM³H]GR-65630 incubation at 25 ℃ for 60 min. Nonspecific binding was assessed in the presence of 10. mu.M MDL-72222. The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]GR-65630. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Serotonin (5-hydroxytryptamine) 5-HT₄

To evaluate the activity of the compounds of the invention in radioligand binding assays, serotonin (5-hydroxytryptamine) 5-HT in 50mM Tris-HCl (pH 7.4) from the striatum of Duncan Hartley guinea pigs was used₄The receptor (Grossman CJ et al Br J Pharmacol (1993), 109: 618). A compound of the present invention is used in combination with 0.7nM³H]GR-113808 was incubated for 30 minutes at 25 ℃. Nonspecific binding was assessed in the presence of 30 μ M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]GR-113808. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Serotonin (5-hydroxytryptamine) 5-HT_5A

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 10mM MgCl) was used₂0.5mM EDTA) expressed by Chinese hamster ovary (CHO-K1) cells, and human recombinant serotonin (5-hydroxytryptamine) 5-HT_5AReceptors (Rees, S. et al, FEBS Lett. (1994), 355: 242). A compound of the present invention is used in combination with 1.7nM ³H]Lysergic acid diethylamide (LSD) was incubated at 37 ℃ for 60 minutes. Nonspecific binding was assessed in the presence of 100. mu.M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]LSD. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and assayedThe percent inhibition of specific binding is shown. Biochemical assay results are shown in table 4 as percent inhibition of specific binding.

Serotonin (5-hydroxytryptamine) 5-HT₆

To evaluate the activity of the compounds of the invention in radioligand binding assays, human recombinant serotonin (5-hydroxytryptamine) 5-HT expressed in human HeLa (HeLa) cells in modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 150mM NaCl, 2mM ascorbic acid, 0.001% BSA) was used₆Receptors (Monsma, FJ.Jr. et al, mol. Pharmacol. (1993), 43: 320). The compounds of the invention were mixed with 1.5nM [3H ]]Lysergic acid diethylamide (LSD) was incubated at 37 ℃ for 120 minutes. Nonspecific binding was assessed in the presence of 5. mu.M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ] ³H]LSD. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 4 as percent inhibition of specific binding.

Serotonin (5-hydroxytryptamine) 5-HT₇

To evaluate the activity of the compounds of the invention in radioligand binding assays, modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 10mM MgCl) was used₂0.5mM EDTA) expressed in Chinese Hamster Ovary (CHO) cells₇Receptors (Roth, B.L. et al, J.Pharmacol. exp. Ther. (1994), 268: 1403; Shen, Y. et al, J.biol. chem. (1993), 268: 18200). A compound of the present invention is used in combination with 5.5nM³H]Lysergic acid diethylamide (LSD) was incubated at 25 ℃ for 2 hours. Nonspecific binding was assessed in the presence of 10. mu.M serotonin (5-HT). The receptor protein is filtered and washed, and then the filtrate is counted to determine the specific binding [ alpha ]³H]LSD. Compounds were screened at 1 μ M or lower concentrations using 1% DMSO as vehicle. Biochemical assay results are shown in table 4 as percent inhibition of specific binding.

Table 4: percent inhibition of ligand binding to an aminergic G protein-coupled receptor by the compounds of the invention:

example B6: serotonin (5-hydroxytryptamine) 5-HT compounds of the invention _2ADetermination of agonist/antagonist Activity

To determine the agonist or antagonist activity of the compounds of the invention in functional assays, human recombinant serotonin 5-HT cells expressed in human embryonic kidney (HEK-293) cells are used_2AReceptors ([ Jerman, J. et al, Eur.J.Pharmacol. (2001), 414: 23-30)]). Cells were suspended in DMEM buffer and dispensed into microwell plates. Cytoplasmic calcium fluorescence indicator (with free cytoplasmic Ca)²⁺Ion concentration was varied proportionally) was mixed with probenecid (probenicid) in HBSS buffer (pH 7.4) supplemented with 20mM HEPES, added to each well, and equilibrated with the cells at 37 ℃ for 30 minutes, followed by equilibration at 22 ℃ for 30 minutes.

To determine agonist effects, a compound of the invention, a reference agonist or HBSS buffer (basal control) is added to the cells and changes in fluorescence intensity are measured using a microplate reader. For the measurement of the stimulated control, 100nM 5-HT was added to individual test wells.

Each result is expressed as a percentage of control response to 100nM 5-HT. The standard reference agonist was 5-HT, several concentrations of which were tested in each assay to obtain a concentration-response curve from which its EC could be calculated ₅₀The value is obtained.

For determining antagonist effects, in fluorescence measurementsPreviously, the compound of the invention, the reference antagonist or HBSS buffer was added followed by 3nM 5-HT or HBSS buffer (basal control). Each result is expressed as a percentage inhibition of the control response to 3nM 5-HT. The standard reference antagonist is ketanserin, which is tested at several concentrations in each assay to obtain a concentration-response curve from which its IC can be calculated₅₀The value is obtained. Compounds were screened at 3 μ M or lower concentrations using DMSO as vehicle.

Example B7: serotonin (5-hydroxytryptamine) 5-HT compounds of the invention₆Determination of agonist/antagonist Activity

To determine agonist or antagonist activity of the compounds of the invention in functional assays, human recombinant 5-HT was used₆Receptors were transfected into CHO cells [ Kohen, r., j. neurohem. (1996), 66: 47]And the activity of the compounds of the present invention was determined by measuring their effect on cAMP production using a homogeneous time-resolved fluorescence (HTRF) assay method. Cells were suspended in HBSS buffer supplemented with 20 mh epes (pH 7.4) and 500 μ M IBMX, then dispensed into microwell plates in the absence (control) or presence of a compound of the invention or a reference agonist or antagonist, and incubated for 45 minutes at 37 ℃.

For agonist assays, 10 μ M5-HT was contained in a separate test well in the stimulated control assay. After incubation, cells were lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (europium cryptate-labeled anti-cAMP antibody) were added. After 60 minutes at room temperature, the fluorescence transfer was measured using a microplate reader at lex ═ 337nm and lem ═ 620 and 665 nm. cAMP concentration was determined by dividing the signal measured at 665nm by the signal measured at 620nm (ratio).

Each result is expressed as a percentage of control response to 10. mu.M 5-HT. The standard reference agonist is 5-HT, which is tested at several concentrations in each assay to obtain a concentration-response curve from which its EC can be calculated₅₀The value is obtained.

For antagonist assays, the reference agonist 5-HT was added at a final concentration of 100 nM. For the basal control assay, the test wells alone did not contain 5-HT. After incubation at 37 ℃ for 45 min, cells were lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (europium cryptate-labeled anti-cAMP antibody) were added.

After 60 minutes at room temperature, the fluorescence transfer was determined as described above. Each result is expressed as a percentage inhibition of the control response to 100nM 5-HT. The standard reference antagonist is methiothepin.

Example B8: dopamine D of compound_2LDetermination of antagonist Activity

To determine agonist or antagonist activity of the compounds of the invention in functional assays, human recombinant dopamine D stably expressed in Chinese Hamster Ovary (CHO) cells was used_2LReceptors (Senoglese et al J Biol Chem. (1990), 265 (8): 4507). The compound of the invention was mixed with membrane (0.1mg/ml) and 10mM GDP in modified HEPES buffer (20mM HEPES, pH 7.4, 100mM NaCl, 10mM MgCl₂1mM DTT, 1mM EDTA) for 20 minutes and adding Scintillation Proximity Assay (SPA) beads for an additional 60 minutes at 30 ℃. By 0.3nM [ 2 ]³⁵S]GTP γ S initiates the reaction and incubate for an additional 15 minutes. A compound of the invention increases by 50% or more (350%) relative to the response of 1mM dopamine³⁵S]GTP γ S binding, indicating that it has dopamine D_2LPossibility of receptor agonist activity. The compound of the present invention is resistant to 10. mu.M dopamine-induced [ alpha ], [³⁵S]Increased inhibition of GTP γ S binding response by 50% or more (350%), suggesting that it has receptor antagonist activity. Compounds were screened at 3 μ M or lower concentrations using 0.4% DMSO as vehicle. The results of the assay are expressed as a percentage of the specific binding response.

Example B9: dopamine D of compound _2SAntagonist Activity

To determine agonist or antagonist activity of the compounds of the invention in functional assays, human recombinant dopamine D stably expressed in Chinese Hamster Ovary (CHO) cells was used_2SReceptors (GillilandSL et al, Nauyn-Schmiedeberg's Archives of Pharmacology (2000), 361: 498). Test compounds were mixed with membrane (0.05mg/ml) and 3. mu.M GDP in modified HEPES buffer (20mM HEPES, pH 7.4, 100mM NaCl, 10mM MgCl)₂1mM DTT, 1mM EDTA) for 20 minutes, followed by addition of Scintillation Proximity Assay (SPA) beads for an additional 60 minutes at 30 ℃. By 0.3nM [ 2 ]³⁵S]GTP γ S initiates the reaction and incubates for an additional 30 minutes. The compound of the present invention increases the [ 2 ], [ 350% ], relative to a response of 100. mu.M dopamine³⁵S]GTP γ S binding, indicating that it has dopamine D_2SPossibility of receptor agonist activity. The compound of the present invention is resistant to 3. mu.M dopamine-induced [ alpha ], [³⁵S]Increased inhibition of GTP γ S binding response by 50% or more (350%), suggesting that it has receptor antagonist activity. Compounds were screened at 3 μ M or lower concentrations using 0.4% DMSO as vehicle. The results of the assay are expressed as a percentage of the specific binding response.

Example B10: in histamine H ₁Determination of agonist or antagonist Activity of Compounds of the invention in functional assays

To determine the agonist or antagonist activity of the compounds of the invention in functional assays, human recombinant histamine H expressed in human embryonic kidney (HEK-293) cells was used₁Receptors (Miller, T.R. et al, J.Biomol. Screen., (1999), 4: 249-258). Cells were suspended in DMEM buffer and then dispensed into microwell plates. Cytoplasmic calcium fluorescence indicator (with free cytoplasmic Ca)²⁺Ion concentration was varied proportionally) was mixed with probenecid (probenicid) in HBSS buffer supplemented with 20mM Hepes (pH 7.4), which was then added to each well and equilibrated with the cells for 30 min at 37 ℃, followed by 30 min at 22 ℃. To determine agonist effects, a compound of the invention, a reference agonist or HBSS bufferA wash (basal control) was added to the cells and changes in fluorescence intensity were measured using a microplate reader. For the determination of the stimulated control, 10 μ M histamine was added to individual test wells.

Each result is expressed as a percentage of the control response to 10 μ M histamine. The standard reference agonist is histamine, several concentrations of which are tested in each assay to obtain a concentration-response curve from which its EC can be calculated ₅₀The value is obtained.

To determine antagonist effects, prior to fluorescence measurements, a compound of the invention, a reference antagonist or HBSS buffer was added, followed by 300nM histamine or HBSS buffer (basal control). Each result is expressed as a percentage inhibition of the control response to 300nM histamine. The standard reference antagonist is ketanserin, which is tested at several concentrations in each assay to obtain a concentration-response curve from which its IC can be calculated₅₀The value is obtained. Compounds were screened at 3 μ M or lower concentrations using DMSO as vehicle.

Example B11: increasing neuronal synaptic growth

Neuronal synaptic growth in cortical neurons

Compounds were tested to determine their ability to stimulate the growth of cortical neuronal synapses. Cortical neurons were isolated using standard methods. To isolate primary rat cortical neurons, embryonic brains from pregnant rats at day 17 of gestation were prepared in Leibovitz medium (L15; Gibco). The cortex was dissected out and the meninges were removed. The cortex C was dissociated using trypsin (Gibco) and DNase I was used. Cells were detached by pipetting in Darber modified eagle medium ("DMEM"; Gibco) containing 10% fetal bovine serum ("FBS") (Gibco) for 30 minutes and centrifuged at 350 Xg for 10 minutes at room temperature. Cells were suspended in Neurobasal medium supplemented with 2% B27(Gibco) and 0.5mM L-glutamine (Gibco). At 37 deg.C, 5% CO ₂Coating cells with 30,000 cells/well in an atmosphere of 95% airpoly-L-lysine was stored on plate. After attachment, vehicle controls and compounds of the invention at various concentrations were added to the medium. BDNF (50ng/mL) was used as a positive control for neurite outgrowth. After treatment, the cultures were washed in phosphate buffered saline ("PBS"; Gibco) and fixed in 2.5% glutaraldehyde in PBS. Cells were fixed after 3 days of growth. Some pictures (about 80) of the neurite-bearing cells were taken with a camera for each case. The pictures were analyzed using software from Image-Pro Plus (france) to determine length. Results are expressed as mean values (s.e.m.). Statistical analysis of the data was performed using one-way analysis of variance (ANOVA).

Neuronal synapse growth in rat mixed cortical cultures

Cortical mixed cultures were prepared from E18 wistar rat embryos. The cortex was dissected out and the tissue was cut into small portions. Cells were separated by 15 min incubation with dnase and papain. Cells were harvested by centrifugation (1500rpm, 5 minutes). The tissue was separated by pipetting and the cells plated in poly-L-lysine coated 48 wells using the micro-islet method (20000 cells in 25 μ L medium) in MEM supplemented with 2mM glutamine, 0.1 μ g/ml gentamicin, 10% heat-inactivated fetal bovine serum (FBS-HI) and 10% heat-inactivated horse serum (HS-HI). After the cells were attached to the wells, 250. mu.l of medium was added to each well. 4 hours after plating, the medium was changed to fresh medium (MEM with supplement and 5% HS-HI) containing test compounds at concentrations of 0.5, 5 and 50 nM. BDNF (50, 100 and/or 150ng/ml) and/or NGF (50ng/ml and/or 100ng/ml) were used as positive controls. After 2 days of in vitro studies, conditioned medium of cells was collected from plates before cell fixation. The medium samples were centrifuged at 13000rpm for 3 minutes to remove cell debris. The samples were stored at-20 ℃ for later analysis. Cells were fixed with formaldehyde and processed for immunocytochemical analysis. The manufacturer (Promega, BDNF Emax) was used ImmunoAssay System, catalog number: g7610) Description of the inventionBDNF levels in conditioned media were determined by BDNF ELISA.

Cultures were fixed with 4% formaldehyde in 0.01M PBS for 30 minutes and washed once with PBS. The fixed cells were first permeabilized and non-specific binding blocked by incubation for 30 min using 1% bovine serum albumin in PBS and 0.3% Triton X-100 in blocking buffer. Rabbit anti-MAP-2 (diluted 1: 1000, AB5622, Chemicon, in blocking buffer) was used as the primary antibody. Cells were incubated with primary antibody at +4 ℃ for 48 hours, washed with PBS, and incubated with secondary antibody, i.e., goat anti-rabbit IgG conjugated to Alexa Fluor568 (1: 200, A11036, molecular probes) at room temperature for 2 hours. The immunopositive cells were visually examined by fluorescence microscopy equipped with a suitable filter plate system and recorded by high resolution image capture. Cells from each area (4 areas per well) were counted and neuronal synaptic growth was quantified using Image Pro Plus software.

The number of wells used per concentration of compound was 6 (n-6). All data are expressed as mean ± Standard Deviation (SD) or mean Standard Error (SEM), and differences at a level of p < 0.05 were considered statistically significant. Statistical analysis was performed using StatsDirect statistical software. Differences between the mean values of each group were analyzed by using one-way ANOVA followed by Dunnet's test (versus vehicle treated group).

Example B12: evaluation of the ability of compounds to enhance cognition, learning and memory in scopolamine treated rats using an in vivo model

A two-test object recognition model in rats developed by Ennaceur and delaour was used as a model of contextual/short-term memory [ Ennaceur, a. et al, behav. brain Res. (1988), 31: 47-59]. The model is based on spontaneous exploration activities of rodents and does not involve rule learning or reinforcement. The new object recognition model is sensitive to the effects of aging and cholinergic dysfunction [ Scali, c, et al, neurosci. letters. (1994), 170: 117-120; bartolini, l. et al, biochem. behav. (1996), 53: 277-283].

Male Sprague-Dawley rats between 6 and 7 weeks of age and weighing 220-300 g were from Centred' Eleviage (Rue Janvier, B.P.55, Le Genest-Saint-Isle 53940, France). Animals were divided into 2-4 groups and placed in polypropylene cages (ground area 1032 cm)²) The method comprises the following steps: at room temperature (22. + -. 2 ℃ C.), the food and water are not restricted in a 12 hour light/12 hour dark cycle. Animals were allowed to acclimate to ambient conditions for at least 5 days before the start of the experiment and were numbered tail with a permanent marker.

The test site was a dark blue square wooden box (60 cm. times.60 cm. times.40 cm) with a 15 cm. times.15 cm black square section beneath the clear plexiglass floor. The field and objects placed within the field were cleaned with water between each trial to remove any rat's remaining olfactory traces. The field was placed in a dark room and illuminated only with halogen bulbs towards the ceiling to obtain a uniform dark light of about 60 lux inside the cabinet. The day before the test, animals were allowed to freely explore the test site for 3 minutes in the presence of two objects (habituation). The animals to be tested were placed in the laboratory room for at least 30 minutes prior to testing.

The new object recognition test consists of two tests, separated by 120 minutes or 24 hours. When a memory-disrupting drug such as the cholinergic antagonist scopolamine is used, the interval between trials is preferably 120 minutes. Alternatively, intervals between trials of 24 hours were used when studying the natural forgetting effect of new object cognitive tasks. In the first or learning test (T)₁) During this period, rats were placed on the field with two identical objects in advance. The time required for each animal to complete a 15 second object study was measured with a 4 minute dwell time. A nose less than 2 centimeters ("cm") from an object or contact with an object is considered an investigation. In a second test or test run (T)₂) During this time, one of the objects present in the first trial is replaced with an unknown or new object, while the second familiar object is left in place. The rats were returned to the field for 3 minutes and the exploration of both objects was determined. T is₁And T₂The locomotor activity of the rats (number of rat crossovers observed under a clear plexiglass floor) was scored during the period. At the end of the experiment, the rats were sacrificed by intraperitoneal administration of an excess of pentobarbital.

As part of a new object recognition task, the following parameter (1) T was measured ₁The time during which 15 seconds of object exploration is completed; (2) t is₁The motion behavior (number of passes) during the session; (3) t is₂The time (T) taken for actively exploring familiar objects_{Familiarity with})；(4)T₂During which the time (T) taken to actively explore a new object_New) (ii) a And (5) T₂The movement behaviour (number of passes) during the period. Evaluation T₂The time and T taken during which a new object is actively explored₂Difference in time (Δ T) during which it takes to actively explore familiar objects_New-T_{Familiarity with}). Also, T in each group is obtained_New-T_{Familiarity with}(ii) animal% greater than or equal to 5 seconds; described in% of excellent learners.

Animals that did not reach the lowest level of object exploration were excluded from the study because they had naturally low levels of spontaneous exploration. Thus, the study only includes exploring the object for at least 5 seconds (T)_New+T_{Familiarity with}> 5 seconds).

Animals were randomly assigned to 14 groups. The compounds of the invention and controls were administered to groups of animals as follows: solutions of the compounds were freshly prepared daily at a concentration of 0.25mg/ml using purified water or saline as vehicle. Donepezil was used as a positive control, and a single saline solution of scopolamine (5mL/kg) freshly prepared daily was administered simultaneously. Scopolamine, purchased from Sigma chemical company (catalog number S-1875; St.Quentin Fallavier, France), was dissolved in saline at a concentration of 0.06 mg/mL.

In learning test (T)₁) Donepezil or its vehicle and scopolamine were administered intraperitoneally 40 minutes prior. Learning test (T)₁) The compound or its vehicle was administered by gavage 25 minutes before, i.e. 5 minutes after scopolamine administration.For compounds administered intraperitoneally, the volume administered was 5ml/kg body weight, and for oral administration 10 ml/kg. The recognition score and the percentage of excellent learners using the compound were determined.

Example B13: determining the ability of a compound to treat, prevent and/or delay the onset and/or progression of schizophrenia in PCP-treated animals using an in vivo model

In vivo models of schizophrenia may be used to determine the ability of the compounds described herein to treat and/or prevent schizophrenia and/or delay its onset and/or progression.

An exemplary model for testing the ability of one or more compounds described herein to treat and/or prevent schizophrenia and/or delay its onset and/or progression uses phencyclidine (PCP), which is administered to an animal (e.g., a non-primate (rat) or primate (monkey)), resulting in a functional disorder similar to that found in those with schizophrenia [ Jentsch et al, Science (1997), 277: 953-; piercey et al, Life Sci, (1988), 43 (4): 375-385]. Standard protocols can be used in this and other animal models. One regimen involves PCP-induced hyperactivity.

Male mice (of a different breed, e.g., C57Bl/6J) from a suitable supplier, e.g., Jackson Laboratories (Bar Harbor, Maine) were used. Obtained were 6 weeks old mice. Upon receipt, mice were tagged with a unique identification number (tail-tagged) and grouped in 4 mice/cage per OPTI mouse ventilated cage. All animals remained grouped during the remainder of the study. All mice were acclimated to the animal room for at least two weeks prior to testing, and subsequently tested for an average age of 8 weeks. During the acclimation period, mice were regularly checked, treated and weighed to ensure adequate health and fitness. Animals were kept in a 12/12 light/dark cycle. The room temperature was maintained at 20 to 23 ℃ and the relative humidity was maintained at 30 to 70%. Food and water were not restricted during the study. In each test, animals were randomly assigned between treatment groups.

Open Field (OF) testing evaluates motor behavior, e.g., determines baseline motor behavior and motor behavior in response to pharmacological agents in mice. The open field box is a square space of plexiglass (27.3 × 27.3 × 20.3 cm; Med Associates Inc., St Albans, VT) surrounded by an infrared beam (16 × 16 × 16) to measure horizontal and vertical motion. The analysis is configured to divide the open field into central and peripheral regions to enable the infrared to measure activity at the center and periphery of the region. The travel distance was measured when the mice moved to disrupt the horizontal beam and the standing activity was measured when the vertical beam was disrupted.

Mice (10 to 12 animals per treatment group) were acclimated for at least 1 hour in an active testing room prior to testing. At each test, 8 animals were tested. Mice were administered vehicle (10% DMSO or 5% PEG200 and 1% tween 80), compound OF the invention, clozapine (positive control, 1mg/kg intraperitoneal), and placed in the OF box for 30 minutes, then injected with water or PCP, and placed back in the OF box for 60 minutes. At the end OF each OF the OF test periods, the OF box was thoroughly cleaned.

Mouse model of PCP hyperactivity of schizophrenia

The desired dose of test compound is dissolved in an appropriate vehicle, e.g., 5% PEG200, 1% tween 80, and administered orally 30 minutes prior to PCP injection. Clozapine (1mg/kg) was dissolved in 10% DMSO and administered intraperitoneally 30 minutes prior to PCP injection. PCP (5mg/kg) was dissolved in a sterile injectable saline solution and administered intraperitoneally.

The data were analyzed by analysis of variance (ANOVA), followed by post hoc comparisons using Fisher's test as appropriate. Baseline activity was determined at the first 30 minutes of testing prior to PCP injection. PCP-induced activity was measured during 60 minutes after PCP injection. Statistical outliers falling above or below 2 standard deviations from the mean were removed from the final analysis. If p < 0.05, the effect is considered significant. A comparison of total distance traveled and total stance was made between the group treated with compound and the group treated with vehicle and positive control clozapine after PCP administration.

Example B14: determining the ability of a compound to treat, prevent and/or delay the onset and/or progression of schizophrenia in amphetamine-treated animals using an in vivo model

Male mice (of a different breed, e.g., C57Bl/6J) from a suitable supplier (e.g., Jackson Laboratories, Bar Harbor, maine) were used. Mice are typically obtained at 6 weeks of age. All mice were acclimated to the animal room for at least two weeks prior to testing. During the acclimation period, mice were regularly checked, treated and weighed to ensure adequate health and fitness. Animals were kept in a 12/12 light/dark cycle. The room temperature was maintained at 20 to 23 ℃ and the relative humidity was maintained at 30 to 70%. Food and water were not restricted during the study. In each test, animals were randomly assigned between treatment groups.

Open Field (OF) test to evaluate locomotor activity. The open field box is a square box of plexiglass (e.g., 27.3 x 20.3 cm; Med Associates Inc., St Albans, VT) surrounded by an infrared beam source (16 x 16). The pens were configured to divide the open field into a central and peripheral region and the photocell beams were positioned to measure activity in and around the OF box. Horizontal activity (distance traveled) and vertical activity (standing) were determined from consecutive beam breaks.

On the day of testing, animals were acclimated in the test room for at least 1 hour prior to treatment. Animals were administered vehicle, haloperidol (positive control, 0.1mg/kg intraperitoneal), test compound, and placed in OF. The time of administration of the test compound to each animal is recorded. Baseline activity was recorded for 30 minutes, after which the mice received amphetamine (4mg/kg) or water and placed back in the OF box for 60 minutes. At the end OF each open field test period, the OF box was thoroughly cleaned. Typically 10 to 12 mice are tested in each group. The test compound dosage range is typically 0.01mg/kg to 60 mg/kg.

The data were analyzed by analysis of variance (ANOVA), followed by post hoc comparisons using Fisher's test as appropriate. Baseline activity was measured during the first 30 minutes of the experiment prior to amphetamine injection. Amphetamine-induced activity was measured during the 60 min period following amphetamine injection. Statistical outliers of up to 2 standard deviations above or below the mean were excluded from the final analysis. If p < 0.05, the effect is considered significant. The total distance traveled and total stance after amphetamine administration were compared between the groups treated with compound and with vehicle and positive control haloperidol.

Example B15: use of in vivo Condition Avoidance Response (CAR) model to determine the ability of a Compound to treat, prevent and/or delay the onset and/or progression of schizophrenia

All currently approved antipsychotic agents (typical and atypical) are known to have the ability to selectively inhibit Conditioned Avoidance Response (CAR) behavior in rats. This phenomenon makes CARs a basic test for evaluating the antipsychotic activity of new compounds.

Rats (multiple species, 2 months of age) were housed and tested in a computer-assisted, bi-directional activity avoidance device (shuttle box). The box comprised two equally sized compartments separated by a stainless steel partition containing a 7 x 7cm opening. Each compartment was fitted with an electrified grid floor made of stainless steel bars spaced 1cm apart. Rats trained to avoid foot shocks were habituated by being left in the shuttle box for 4 minutes each day, followed by 30 trials, with randomized intervals of 20 to 30 seconds between each trial. Each trial included a 10 second stimulation light (conditioned stimulation, CS) followed by a 10 second foot shock in the presence of light in the compartment where the rats were located (unconditioned stimulation, US). If the animal leaves the compartment before the foot shock is given, the response is considered to be an avoidance response. If the rat did not change the compartment during the 10 second light stimulation and during the 10 second shock + light stimulation, the escape failure was recorded. The test requires that the animals be trained for 5 days/week. On each training day, rats were subjected to one training session of 30 trials. Test compound treatment was initiated only when rats reached at least 80% avoidance performance during at least two consecutive training sessions. The test compounds were administered orally at different doses and different pretreatment times (depending on the specific pharmacokinetic properties).

Compounds with antipsychotic properties inhibit conditioned avoidance responses, with or without increased escape failure. Each dose of the administered test compound was analyzed with vehicle control treated rats using Friedman two-way analysis of variance (ANOVA) for statistical analysis, followed by Wilcoxon paired sign rank test. Various concentrations of the compounds of the invention were evaluated for their ability to bind to the receptors described herein above.

Example B16 determination of the ability of Compounds to increase attention/alertness and decrease Impulse Using a five-choice sequential reaction task (5-choice sequential reaction task)

Attention and impulsivity are characteristic of a variety of disease states. Continuous Performance Test (CPT) used in humans is able to detect attention deficit in a variety of diseases, including attention deficit hyperactivity disorder [ Riccio et al, j.neuropsychiatry clin.neurosci. (2001), 13 (3): 326-335], schizophrenia [ Lee, et al, schizoph. res. (2006), 81 (2-3): 191-197] and mild cognitive impairment [ Levinoff et al, Neuropsychology (2006), 20 (1): 123-132]. Preclinical simulation (analogue) of CPT a continuous response time task [ "5-CSRTT" was selected for five items; robbins, t., Psychopharmacology (2002), 3-4: 362-380]. In this operative experiment, rats were asked to focus and maintain a response, they looked at 5 wells and a brief stimulating light was present in one of the 5 wells. The short illumination of the spike light in 5-CSRTT is similar to the presentation of the "correct" letter in human CPT. When observing the stimulating light, the rat must poke the responding hole with the nose to get a food reward. 5-CSRTT enables measurements that are similar behavioral responses to CPT, including accuracy, response speed, and mandatory responses. In this study, drug trials were conducted with a change in trial parameters that resulted in an improved early response. This early response is postulated to be predictive of impulsivity, i.e. failure to overcome inappropriate responses, indicating sensitivity to tomoxetine (atomoxetine) [ Navarra, et al prog. 34-41].

A minimum of 12 male Long-Evans rats (275-300g) were obtained from Harlan Laboratories, Indianapolis, IN. At the start of the experiment, the rats were approximately 16-18 months old and, upon arrival, the rats were assigned a unique identification number (tail marker). Rats were housed individually in OptiRAT cages and acclimatized for a period of 7 days prior to the start of a food restriction regimen of: rats were given 85% of free feed corresponding to the age of the rats to control body weight, and about 10-20g of the rat feed was administered per day. Water was ad libitum except during the test period. Animals were maintained in a 12/12H light/dark cycle environment (lights on 0700 EST), room temperature was maintained at 22 + -2 deg.C, and relative humidity was maintained at about 50%. All animals were examined, treated and weighed prior to starting the test to ensure adequate health and fitness to minimize non-specific stress associated with the test. The 5-CSRTT project was performed during the light phase of the animals. All experiments and procedures were approved by the Institutional Animal Care and UseCommitee of PsychoGenics, Inc.

Equipment: the equipment consists of an aluminum and plexiglass chamber (31.5 cm wide, 25.0m deep, 33.0cm high) with a meshed floor, enclosed in a sound-damping cabinet. Each cabinet is equipped with a low noise extraction fan which may also help to mask external noise. The left wall of each chamber is concavely curved with 5 holes evenly distributed and located about 2.5cm from the floor. Each well was fitted with a standard 3W LED lamp for transmitting a laser light. The opposite wall was fitted with a food box located about 3.0cm from the floor. Each room was illuminated with 3W room light, centered on the ceiling. After each test period, the equipment was cleaned with 70% ethanol.

The test steps are as follows: training: the animal was trained to look at 5 holes emitting stimulating light illumination. Each test session was initiated by room light illumination and food rewards were delivered to the box. The first test started when the rat opened the food box to obtain a food mass. One of the stimulation lights is illuminated for 500msec after an inter-three interval (ITI). Rats must poke the illuminated hole with the nose within 5sec of the stimulating light illumination. Such a response is defined as a correct response, using the food pieces as a reward. The next trial was started after collecting the food pieces. A nasal stamp response to a non-illuminated aperture (false response) or a 5sec restriction followed by a nasal stamp (missed test) resulted in termination of the test, with room light disappearing and forced into a timeout period. And (3) testing: after obtaining a 5-CSRTT of high accuracy (at least 75% correct, at least 50 trials completed per trial period), the drug trial is started. Animals were treated with test compound (different doses, appropriate vehicle), vehicle and positive control (tomoxetine 1mg/kg ip). The ITI varied during drug trials between durations of 10, 7, 5 or 4sec, and was divided into 4 trial groups (each of which included 1 trial in a random fashion for each ITI duration). The test period ended after 60 minutes had elapsed. All rats received drug treatment according to the randomized intra-group design. Drug trials were conducted on wednesday and friday of each week only when rats had completed at least 75% of the correct trials in a minimum of 50 trials during the previous trial period.

The measurements obtained during the test period were: (1) the percent correct, defined as the number of correct trials x 100 divided by the total number of correct and false trials, (2) missed trials, defined as more than 5sec. limit hold response or no response, (3) correct latency, defined as the time required to respond correctly after stimulating illumination, (4) food box latency, defined as the time required to access the food box to take a food block after responding correctly, (5) early response, defined as the total number of responses with nasal stamps during ITI, and (6) sustained response, defined as the total number of additional responses made after initial nasal stamping.

Statistical analysis

Data expressed as percent correct; number of missed trials, number of preliminary responses and number of sustained responses; and the waiting time (sec.) required to respond correctly and to take a food piece after a correct response. Data were analyzed by analysis of variance (ANOVA). In the case of use, values of p < 0.05 are considered to be significant. Post hoc comparisons were made using Fisher LSD post hoc analysis, if appropriate.

Example B17: animal models of negative symptoms of schizophrenia: sub-chronic PCP-induced social deficits

Phencyclidine (PCP) administered to humans and experimental animals induces a wide range of schizophrenia symptoms, including negative symptoms and cognitive deficits. As part of a series of negative symptoms, the primary symptom of schizophrenia is considered social isolation/social avoidance. Sub-chronic treatment of rats with PCP resulted in the appearance of significant signs of social avoidance as measured by lack of time to encounter with rats intruding into the cage. Male sprague-dawley rats (approximately 150g, from a different supplier, e.g. Harlan, indiana) were used in this study. Upon receiving the rats, they were housed in groups in OPTI rat ventilation cages. Rats were housed in groups of 2-3 per cage for the remainder of the study. During the acclimation period, rats are regularly checked, managed and weighed to ensure adequate health and fitness. Rats were maintained under a 12/12 light/dark cycle and were lit at 7:00 in the morning. The room temperature is maintained at 20-23 deg.C, and the relative humidity is maintained at 30-70%. Ad libitum food and water was provided during the study. Animals were randomly assigned to treatment groups and balanced by age.

Rats were injected twice daily with either PCP (2 mg/kg; subcutaneous injection) or saline (subcutaneous injection) for five days prior to testing. On day 6, after pre-treatment with vehicle, clozapine as a positive control (2.5mg/kg, i.e. intraperitoneal injection in 5% PEG: 5% Tween 80) and the expected dose of test compound in the appropriate vehicle for 30 minutes, a pair of rats unfamiliar with each other receiving the same treatment were placed in the open area of white plexiglas (24 ". times.17". times.8 ") and allowed to interact with each other for 6 minutes. Social interactions ('SI') include: sniffing the other rat; hair is managed for another rat; climbing over or under or around another rat; followed another rat; or explore the perineum of another rat. Passive contact and aggressive contact are not considered a measure of social interaction. In the 6 minute test, the time spent by the rats in dealing with each other was recorded by a trained observer. Between different rat tests, the social contact box was thoroughly cleaned. Data were analyzed by analysis of variance (ANOVA), followed by post-hoc analysis (e.g., Fischer, Dunnett) as appropriate. If p < 0.05, the effect is considered significant.

Example B18: animal models of extrapyramidal syndrome (EPS): measuring catalepsy in the mouse rod test

Antipsychotics are known to induce extrapyramidal syndrome (EPS) in animals and humans. An animal model believed to be useful for predicting EPS is the mouse steel bar test, which measures the catalepsy response to pharmacologically active agents. Male mice (different strains) from appropriate suppliers (e.g. Jackson Laboratories (Bar Harbor, Maine)) were used. Mice were received at 6 weeks of age. Upon receipt, mice were assigned a unique identification number (tail marker) and group housed in OPTI mouse ventilated cages with 4 mice per cage. Mice remained housed in 4 per group for the remainder of the study. All mice were acclimated to the new room for at least two weeks prior to testing, and then tested at an average age of 8 weeks. During the acclimation period, mice were regularly checked, managed and weighed to ensure adequate health and fitness. Mice were maintained under a 12/12 light/dark cycle. The room temperature is maintained at 20-23 deg.C, and the relative humidity is maintained at 30-70%. Ad libitum food and water was provided during the study. In each test, animals were randomly assigned to treatment groups.

In the mouse steel rod test, the front paw of the mouse is placed on a 2 "raised horizontal rod on a plexiglas platform, and a maximum of 30 seconds is recorded for each test. The test was terminated when the animal's forepaws returned to the platform or after 30 seconds. The test was repeated 3 times and the average of 3 trials was recorded as an indicator of catalepsy. In these studies, a typical antipsychotic drug haloperidol (2mg/kg, intraperitoneal, dissolved in 10% DMSO) was used as a positive control, inducing catalepsy and catalepsy, as measured by the time of retention on the stick. 30 minutes prior to the test, the desired dose of the test compound is dissolved in a suitable vehicle and administered orally, and the vehicle and positive control haloperidol (2mg/kg, intraperitoneal) are administered to additional groups of mice. Catalepsy responses were measured 30 minutes, 1 hour, and 3 hours after treatment. During the 30 second trial, a trained observer measured the time of hold on the bar. Data were analyzed by analysis of variance (ANOVA), followed by post hoc analysis (e.g., Fischer, Dunnett) as appropriate. If p < 0.05, the effect is considered significant.

Example B19: animal model for testing anxiolytic effects of compounds using the Elevated Plus Maze (EPM) assay

This study can be used to test the anxiolytic properties of the compounds detailed herein using the Elevated Plus Maze (EPM) assay in C57Bl/6J mice.

Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Maine) were used for open field studies. Mice were received at 6 weeks of age. Upon receipt, mice were assigned a unique identification number (tail marker) and group housed in OPTI mouse ventilated cages with 4 mice per cage. Mice remained housed in 4 per group for the remainder of the study. All mice were acclimated to the new room for about two weeks prior to testing, followed by testing at an average age of 8 weeks. During the acclimation period, mice were regularly checked, managed and weighed to ensure adequate health and fitness. Animals were maintained in a 12h/12h light/dark cycle. The room temperature is maintained at 20-23 deg.C, and the relative humidity is maintained at 30-70%. Ad libitum food and water was provided during the study. In each test, animals were randomly assigned to treatment groups. All animals were euthanized at the end of the study.

The compound is soluble in 5% PEG200/H₂In the presence of oxygen in the atmosphere of O,orally administered 30 minutes prior to the test in a dose volume of 10 mL/kg; 2) diazepam (2.5mg/kg) was dissolved in 45% hydroxypropyl- β -cyclodextrin and administered orally 30 minutes prior to the trial in a dose volume of 10 mL/kg.

The elevated plus maze test evaluates anxiety. The maze (Hamilton Kinder) consists of two closed arms (14.5cm high by 5cm wide by 35cm long) and two open arms (6cm wide by 35cm long) forming a cross with a square central platform (6X 6 cm). All visible surfaces are made of black acrylic. Each arm of the maze is placed on a support column 56cm above the floor. An antistatic black vinyl curtain (7 'high) surrounds the EPM, forming a 5' x 5 "fence. Before testing, animals were brought into the test room for acclimation for at least 1 hour. The animals were placed in the center of the elevated plus maze facing the closed arms and a 5 minute circulation (run) was performed. All animals were tested once. The time spent, distance traveled and number of entries into each arm were automatically recorded by the computer. EPM was thoroughly cleaned after each mouse.

Data were analyzed by analysis of variance (ANOVA), followed by Fisher's LSD post hoc analysis as appropriate. If p < 0.05, the effect is considered significant.

All documents cited herein, such as publications, patents, patent applications, and published patent applications, are incorporated by reference herein in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious to those skilled in the art that certain minor changes and modifications may be practiced. Accordingly, the description and examples provided should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R¹and R^2aTogether forming an ethylene radical (-CH)₂CH₂-)；

R^2bIs H or unsubstituted C₁-C₈An alkyl group;

each R^3aAnd R^3bIndependently is H or unsubstituted C₁-C₈An alkyl group;

each R^10aAnd R^10bIs H;

each X⁷、X⁸、X⁹And X¹⁰Independently is CR⁴；

Each R⁴Independently H, halogen or unsubstituted C₁-C₈An alkyl group;

m is 1 and q is 0;

n is 1;

each R^8c、R^8d、R^8eAnd R^8fIndependently is H, hydroxy or unsubstituted C₁-C₈Alkyl, or with geminal R^8(c-f)Together form a methylene group, or, with a geminal R^8(c-f)And the carbon atoms to which they are attached together form a carbonyl group, or together with a vicinal R^8(c-f)Together form a bond, with the proviso that when R^8(c-f)Is and is vicinal to R^8(c-f)Twin R when taken together to form a bond^8(c-f)Is not a hydroxyl group;

q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino; wherein

Each "unsubstituted aryl" is phenyl or naphthyl,

each "substituted aryl" refers to a phenyl group having 1 to 5 substituents independently selected from the group consisting of: c₁-C₈Alkoxy, halogen and C₁-C₈An alkyl group, a carboxyl group,

each "substituted heteroaryl" refers to a heteroaryl having 1 to 5 substituents independently selected from the group consisting of: phenyl, halogen and substituted or unsubstituted C ₁-C₈An alkyl group, a carboxyl group,

each of said "substituted C₁-C₈Alkyl "refers to C having 1 to 5 substituents selected from halogen₁-C₈An alkyl group, a carboxyl group,

each "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 3 substituents independently selected from the group consisting of: c₁-C₈An alkyl group, a carboxyl group,

each "substituted or unsubstituted amino" is independently-NR_aR_bWherein (a) R_aAnd R_bEach independently selected from: h and C₁-C₈An alkyl group; or (b) R_aAnd R_bTogether with the nitrogen atom forming a heterocyclic ring or by C₁-C₈An alkyl-substituted heterocyclic ring, which is substituted with an alkyl group,

the heteroaryl group means an unsaturated aromatic carbocyclic group having 2 to 10 ring carbon atoms and at least one ring heteroatom selected from heteroatoms of nitrogen, oxygen and sulfur, and which has a single ring;

the heterocyclic group refers to a saturated non-aromatic group having a single ring and having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from nitrogen, sulfur or oxygen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X⁷、X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X⁸And X¹⁰Is CR⁴Wherein R is⁴Is H; x⁹Is CR⁴And R is^8cAnd R^8dAre all H.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^2b、R^10a、R^10b、R^3aAnd R^3bAre all H.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least X⁷、X⁸、X⁹And X¹⁰One is CR⁴Wherein R is⁴Is not H.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X⁷、X⁸And X¹⁰Are all CR⁴Wherein R is⁴Is H, X⁹Is CR⁴Wherein R is⁴Is unsubstituted C₁-C₈An alkyl group.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein at least R^8c－R^8fOne is not H.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Q is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Q is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl.

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

wherein R is⁴Is unsubstituted C₁-C₈An alkyl group;

R^8eand R^8fIndependently H, OH or CH₃(ii) a And is

Q is substituted or unsubstituted aryl or heteroaryl;

the premise is that: when X is present⁷Is CR⁴Wherein R is⁴When is H, R^8eIs OH and R^8fIs H or CH₃。

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein Q is substituted or unsubstituted pyridyl.

12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is of formula (Ii-5), (Ii-6), or (Ii-7):

Wherein R is⁴Is unsubstituted C₁-C₈An alkyl group;

R⁹is H or CH₃(ii) a And is

R^8fIs H or CH₃。

13. A compound of formula (A) or a pharmaceutically acceptable salt thereof:

wherein:

R¹and R^2aTogether forming an ethylene radical (-CH)₂CH₂-)；

R^2bIs H;

each R^3aAnd R^3bIs H;

each R^10aAnd R^10bIs H;

each X⁷、X⁸、X⁹And X¹⁰Independently is CR⁴；

Each R⁴Independently H, halogen or unsubstituted C₁-C₈An alkyl group;

m and q are 0;

each R¹¹And R¹²Independently is H or unsubstituted C₁-C₈Alkyl radical andthe bond representing the presence of an E or Z double bond configuration, or R¹¹And R¹²Together form a bond;

q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; wherein

Each "unsubstituted aryl" is phenyl or naphthyl,

each "substituted heteroaryl" refers to a heteroaryl having 1 to 5 substituents independently selected from the group consisting of: phenyl, halogen and C₁-C₈An alkyl group, a carboxyl group,

the heteroaryl group means an unsaturated aromatic carbocyclic group having 2 to 10 ring carbon atoms and at least one ring heteroatom selected from heteroatoms of nitrogen, oxygen and sulfur, and which has a single ring.

14. A compound, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

15. A compound, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

16. a pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

17. Use of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cognitive disorder, a psychiatric disorder, a neurotransmitter-mediated disorder, or a neuronal disorder in a subject.

18. A kit comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and instructions for use in treating a cognitive disorder, a psychiatric disorder, a neurotransmitter-mediated disorder, or a neuronal disorder.