WO2017151449A1

WO2017151449A1 - M1 receptor positive allosteric modulator compounds and methods of use thereof

Info

Publication number: WO2017151449A1
Application number: PCT/US2017/019566
Authority: WO
Inventors: Douglas Corey BESHORE; Scott D. Kuduk; Subhendu Kumar MOHANTY; Prashant R. LATTHE
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2016-03-04
Filing date: 2017-02-27
Publication date: 2017-09-08

Abstract

The present invention is directed to compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein Q, X, Y, Z, R¹, R⁷ and n are defined herein. The compounds of Formula (I) are M1 receptor positive allosteric modulators that are useful in the treatment of diseases in which the M1 receptor is involved, including Alzheimer's disease, schizophrenia, pain and sleep disorders. The invention also relates to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, and to methods of using the compounds of Formula (I) in the treatment of diseases mediated by the M1 receptor.

Description

TITLE OF THE INVENTION

M1 RECEPTOR POSITIVE ALLOSTERIC MODULATOR COMPOUNDS AND METHODS OF USE THEREOF FIELD OF THE INVENTION

The invention relates to compounds of Formula (I), which are muscarinic M1 receptor positive allosteric modulators, and pharmaceutically acceptable salts thereof, and methods of use of the compounds and salts for the treatment of Alzheimer’s Disease and/or other diseases mediated by the muscarinic M1 receptor. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.

62/303,419447 filed March 4, 2016, the contents of which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION

Alzheimer’s Disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain,

neurofibrillary tangles, and accumulation of the amyloid β peptide (Aβ). Aβ is a 39-43 amino acid peptide produced in the brain by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme (“beta secretase” or“BACE”) and gamma-secretase. The processing leads to accumulation of AE in the brain.

Cholinergic neurotransmission involves the binding of acetylcholine either to the nicotinic acetylcholine receptor (nAChR) or to the muscarinic acetylcholine receptor (mAChR). It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer’s Disease. Consequently, acetyl cholinesterase inhibitors, which inhibit acetylcholine hydrolysis, have been approved in the United States for use in the treatment of the cognitive impairments of Alzheimer’s Disease patients. While acetyl cholinesterase inhibitors have provided some cognitive enhancement in Alzheimer’s Disease patients, the therapy has not been shown to change the underlying disease pathology.

A second potential pharmacotherapeutic target to counteract cholinergic hypofunction is the activation of muscarinic receptors. Muscarinic receptors are prevalent throughout the body. Five distinct muscarinic receptors (M1-M5) have been identified in mammals. In the central nervous system, muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions. The muscarinic M1 receptor, which is prevalent in the cerebral cortex, hippocampus and striatum, has been found to have a major role in cognitive processing and is believed to have a role in the pathophysiology of Alzheimer’s Disease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001, 22(8): 409-414.

In addition, unlike acetyl cholinesterase inhibitors, which are known to provide only symptomatic treatment, M1 agonists also have the potential to treat the underlying disease mechanism of Alzheimer’s Disease. The cholinergic hypothesis of Alzheimer’s Disease is linked to both β-amyloid and hyperphosphorylated tau protein. Formation of β-amyloid may impair the coupling of the muscarinic receptor with G-proteins. Stimulation of the M1 muscarinic receptor has been shown to increase formation of the neuroprotective αAPPs fragment, thereby preventing the formation of the Aβ peptide. Thus, M1 agonists may alter APP processing and enhance αAPPs secretion. See Fisher, Jpn J Pharmacol, 2000, 84:101-112. However, M1 ligands which have been developed and studied for Alzheimer’s Disease have produced side effects common to other muscarinic receptor ligands, such as sweating, nausea and diarrhea. See Spalding et al., Mol Pharmacol, 2002, 61(6): 1297-1302. See also

WO2005056552, WO2005030188 and WO2007067489.

The muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites. See, e.g., S. Lazareno et al., Mol Pharmacol, 2002, 62(6): 1491-1505; S. Lazareno et al., Mol Pharmacol, 2000, 58: 194-207. SUMMARY OF THE INVENTION

In one aspect, the resent invention rovides com ounds having the Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein: each occurrence of X is CR^6AR^6B, or alternatively, up to two occurrences of X are C=O, O, S or NR⁶ and the other occurrences of X, when present, are CR^6AR^6B;

each occurrence of Y is CR^6AR^6B;

each occurrence of R^6Aand R^6B is independently selected from hydrogen, fluorine, ^–O-C ₁ ^-C ₆ ^{alkyl, and -C} ₁ ^-C ₆ ^{alkyl, wherein said–O-C} ₁ ^-C ₆ ^{alkyl and -C} ₁ ^-C ₆ ^{alkyl are optionally} substituted with one to four substituents, independently selected from fluorine,–C₁-C₆ alkyl, and ^–OC ₁ ^-C ₆ ^alkyl;

Q is CH or N;

R⁶ is hydrogen, halogen,–OH,–O-C₁-C₆alkyl, -C₁-C₆alkyl,–S(=O)_k-R²,–C₂- C₆alkenyl,–CN, -C(=O)-(O)_m-R⁴,–N(R^3A)(R^3B), -C₆-C₁₀aryl, -C₅-C₁₀heteroaryl, -C₅- C₁₀heterocycloalkyl, or -OC(=O)-R⁴, wherein said–O-C₁-C₆alkyl, -C₁-C₆alkyl,–C₂-C₆alkenyl, - C₆-C₁₀aryl, -C₅-C₁₀heteroaryl and -C₅-C₁₀heterocycloalkyl are optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆alkyl, and–OC₁-C₆alkyl;

each occurrence of Z is independently CR⁸ or N;

each occurrence of R⁷ and R⁸ are independently hydrogen or halogen; R¹ is selected from the group consisting of:

(a) hydrogen,

(b) a 6-membered aryl,

(c) a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N, S, and O,

(d) halogen,

(e)–CN,

(f)–O-C₁-C₆alkyl,

(g)–C₁-C₆alkyl,

(h)–C₂-C₆alkenyl,

(i)–S(=O)_k–R²,

(j)–(C(O)O)_mN(R^3A)(R^3B),

(k)–OH,

(l) =O, and

(m) -C(=O)-(O)_m–R⁴,

wherein said 6-membered aryl, 5- or 6-membered heteroaryl,–O-C₁-C₆alkyl,–C₁-C₆alkyl and– C₂-C₆alkenyl are optionally substituted with one to three substituents, independently selected from halogen,–OH,–O-C₁-C₆alkyl,–C₁-C₆alkyl, -C(=O)-(O)_m–R⁴,–N(R^3A)(R^3B), and–S(=O)_k– R⁵;

R², R⁴, and R⁵ are independently selected from the group consisting of: hydrogen, –C₁-C₆alkyl,–C₂-C₆alkenyl,–(CH₂)_k-aryl, and–N(R¹)₂, wherein said–C₁-C₆alkyl and–(CH₂)_k- aryl are optionally substituted with up to four halogen,–CN, or–O-C_1-6alkyl, wherein said–O- C₁-C₆alkyl is optionally substituted with one to three halogen;

R^3A and R^3B are independently selected from the group consisting of:

(1) hydrogen,

(2)–C_1-C₆alkyl,

(3)–C_3-C₆cycloalkyl,

(4)–C(=O)-O- R⁴, and

(5)–S(O)₂-R⁴,

or, alternatively, R^3A and R^3B are linked together with the nitrogen to which they are both attached to form a 3- to 6-membered nitrogen-containing heterocyclic ring optionally having one to three additional heteroatoms selected from N, S and O;

n is 0, 1 or 2;

k is 0, 1 or 2; and

m is 0 or 1;

with the proviso that:

(a) where R¹ is 1-methylpyrazol-4-yl, one occurrence of Z is N, and the other occurrence of Z is CH, Q is CH, both occurrences of R⁷ are hydrogen, and each occurrence of X and Y are CH₂, n cannot be 1;

(b) where R¹ is chloro, one occurrence of Z is N, and the other occurrence of Z is CH, Q is CH, both occurrences of R⁷ are hydrogen, and each occurrence of X and Y are CH₂, n cannot be 1; and

(c) where R¹ is hydrogen, one occurrence of Z is N, and the other occurrence of Z is CH, Q is CH, both occurrences of R⁷ are hydrogen, and each occurrence of X and Y are CH₂, n cannot be 1.

The Compounds of Formula (I), (IA), and (IB), and pharmaceutically acceptable salts thereof, can be useful, for example, as M1 receptor positive allosteric modulators, and/or for treating or preventing diseases or disorders in which the M1 receptor is involved, e.g.

Alzheimer’s disease.

The invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the M1 receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by

administering to the patient a therapeutically effective amount of a compound of Formula (I), (IA) or (IB), or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions which include an effective amount of a compound of Formula (I), (IA), or (IB) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

The details of the invention are set forth in the accompanying detailed description set forth below.

Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention, which are muscarinic M1 receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer’s Disease and other diseases mediated by the muscarinic M1 receptor.

In each of the various embodiments of the compounds of the invention described herein, each variable including those of Formulas (I), (IA), and (IB), and the various

embodiments thereof, is selected independently of the others unless otherwise indicated.

The present invention encompasses all compounds of Formulas (I), (IA), and (IB), and the various embodiments thereof, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof. The Compounds of Formula (I)

In one aspect, the present invention includes compounds of Formula I:

(I) or a pharmaceutically acceptable salt thereof, wherein Q, X, Y, Z, R¹, R⁷ and n are as defined above (in the Summary of the Invention) for the Compounds of Formula (I); wherein the compounds may be suitable for use for the treatment of diseases mediated by the muscarinic M1 receptor, e.g. Alzheimer’s disease.

A first embodiment of the invention (Embodiment E1) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein, Q, X, Y, Z, R¹, R⁷ and n are as originally defined (i.e. as defined in Formula (I) in the Summary of the Invention).

A second embodiment (Embodiment E2) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is CH, and all other variables are as defined in Embodiment E1.

A third embodiment (Embodiment E3) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is N, and all other variables are as defined in Embodiment E1.

A fourth embodiment (Embodiment E4) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, both occurrences of Y are CH₂, and all other variables are as defined in Embodiment E1.

A fifth embodiment (Embodiment E5) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, one occurrence of Y is CH₂, and one occurrence of Y is CF₂, and all other variables are as defined in Embodiment E1.

A sixth embodiment (Embodiment E6) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, one occurrence of Y is CH₂, and in the other occurrence of Y, R^6A is hydrogen and R^6B is fluorine, and all other variables are as defined in Embodiment E1.

A seventh embodiment (Embodiment E7) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, in one occurrence of Y, either R^6A or R^6B is–O-C₁-C₆ alkyl, optionally substituted with one to ^{four substituents independently selected from fluorine,–C} ₁ ^-C ₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^{alkyl, and all} other variables are as defined in Embodiment E1.

An eighth embodiment (Embodiment E8) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, in one occurrence of Y, either R^6A or R^6B is -C₁-C₆ alkyl, optionally substituted with one to four ^{substituents independently selected from fluorine,–C} ₁ ^-C ₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^{alkyl, and all other} variables are as defined in Embodiment E1 A ninth embodiment (Embodiment E9) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is 0, and all other variables are as defined in Embodiment E1.

A tenth embodiment (Embodiment E10) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is 1, and all other variables are as defined in Embodiment E1.

An eleventh embodiment (Embodiment E11) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is 2, and all other variables are as defined in Embodiment E1.

A twelfth embodiment (Embodiment E12) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, each occurrence of X is CH₂, and all other variables are as defined in Embodiment E1.

A thirteenth embodiment (Embodiment E13) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or two occurrences of X are C=O, and the other occurrences of X, when present, are CR^6AR^6B and all other variables are as defined in Embodiment E1.

A fourteenth embodiment (Embodiment E14) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or two occurrences of X are O, and the other occurrences of X, when present, are CR^6AR^6B and all other variables are as defined in Embodiment E1.

A fifteenth embodiment (Embodiment E15) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or two occurrences of X are S, and the other occurrences of X, when present, are CR^6AR^6B and all other variables are as defined in Embodiment E1.

A sixteenth embodiment (Embodiment E16) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or two occurrences of X are NR⁶, and the other occurrences of X, when present, are CR^6AR^6B and all other variables are as defined in Embodiment E1.

In a sub-embodiment of Embodiment E16, R⁶ is halogen.

In a further sub-embodiment of Embodiment E16, R⁶ is hydroxy.

In another sub-embodiment of Embodiment E16, R⁶ is–O-C₁-C₆ alkyl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ alkyl, and ^–OC ₁ ^-C ₆ ^alkyl.

In yet another sub-embodiment of Embodiment E16, R⁶ is -C₁-C₆ alkyl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^alkyl.

In another sub-embodiment of Embodiment E16, R⁶ is–S(=O)_k-R², and all other variables are as defined in Embodiment E1.

In a still further sub-embodiment of Embodiment E16, R⁶ is–C₂-C₆ alkenyl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^alkyl.

In a sub-embodiment of Embodiment E16, R⁶–CN.

In another sub-embodiment of Embodiment E16, R⁶–N(R^3A)(R^3B), and all other variables are as defined in Embodiment E1.

In a further sub-embodiment of Embodiment E16, R⁶ is -C₆-C₁₀ aryl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ alkyl, and ^–OC ₁ ^-C ₆ ^alkyl.

In another sub-embodiment of Embodiment E16, R⁶ -C₅-C₁₀ heteroaryl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^alkyl.

In a sub-embodiment of Embodiment E16, R⁶ is -C₅-C₁₀ heterocycloalkyl, optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^alkyl.

In a sub-embodiment of Embodiment E16, R⁶ is -OC(=O)-R⁴, and all other variables are as defined in Embodiment E1.

A seventeenth embodiment (Embodiment E17) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one occurrences of X is–N-C(=O)-(O)_mR⁴, and the other occurrences of X, when present, are CH₂ and all other variables are as defined in Embodiment E1.

An eighteenth embodiment (Embodiment E18) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one occurrences of X is–NH, and the other occurrences of X, when present, are CH₂ and all other variables are as defined in Embodiment E1.

A nineteenth embodiment (Embodiment E19) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one occurrences of X is as defined in any of Embodiments E12-E18, both occurrences of R⁷ are hydrogen, and all other variables are as defined in Embodiment E1.

A twentieth embodiment (Embodiment E20) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, both occurrences of R⁷ are halogen, and all other variables are as defined in Embodiment E1.

A twenty-first embodiment (Embodiment E21) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, one occurrence of R⁷ is hydrogen and one occurrence of R⁷ is halogen, and all other variables are as defined in Embodiment E1.

A twenty-second embodiment (Embodiment E22) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, one occurrence of R⁷ is hydrogen and one occurrence of R⁷ is fluorine, and all other variables are as defined in Embodiment E1.

A twenty-third embodiment (Embodiment E23) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, both occurrences of R⁷ are fluorine, and all other variables are as defined in Embodiment E1.

A twenty-fourth embodiment (Embodiment E24) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, one occurrence of R⁷ is hydrogen and one occurrence of R⁷ is bromine, and all other variables are as defined in Embodiment E1.

A twenty-fifth embodiment (Embodiment E25) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, one occurrence of R⁷ is hydrogen and one occurrence of R⁷ is chlorine, and all other variables are as defined in Embodiment E1.

A twenty-sixth embodiment (Embodiment E26) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, both occurrences of R⁷ are chlorine, and all other variables are as defined in Embodiment E1.

A twenty-seventh embodiment (Embodiment E27) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, both occurrences of Z are CR⁸, and all other variables are as defined in Embodiment E1.

In another sub-embodiment of Embodiment E27, one occurrence of R⁸ is H and one occurrence of R⁸ is Cl.

In yet another sub-embodiment of Embodiment E27, one occurrence of R⁸ is H and one occurrence of R⁸ is Br.

In an additional sub-embodiment of Embodiment E27, both occurrences of R⁸ are Cl.

In another sub-embodiment of Embodiment E27, both occurrences of R⁸ are Br. A twenty-eighth embodiment (Embodiment E28) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, both occurrences of Z are CH, and all other variables are as defined in Embodiment E1.

A twenty-ninth embodiment (Embodiment E29) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, both occurrences of Z are N, and all other variables are as defined in Embodiment E1.

A thirtieth embodiment (Embodiment E30) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, both occurrences of Z are C-F, and all other variables are as defined in Embodiment E1.

A thirty-first embodiment (Embodiment E31) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, one occurrences of Z is CH and one occurrence of Z is C-F, and all other variables are as defined in Embodiment E1.

A thirty-second embodiment (Embodiment E32) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, one occurrences of Z is CR⁸ and one occurrence of Z is N, and all other variables are as defined in Embodiment E1.

In a sub-embodiment of Embodiment E32, one occurrence of Z is CH.

In another sub-embodiment of Embodiment E32, one occurrence of Z is C-F. In a further sub-embodiment of Embodiment E32, one occurrence of Z is C-Cl. In another sub-embodiment of Embodiment E32, one occurrence of Z is C-Br. A thirty-third embodiment (Embodiment E33) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is hydrogen and all other variables are as defined in Embodiment E1.

A thirty-fourth embodiment (Embodiment E34) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is a 6-membered aryl, optionally substituted with one to three substituents, independently selected ^{from halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, -C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), and– S(=O)_k–R⁵, and all other variables are as defined in Embodiment E1.

A thirty-fifth embodiment (Embodiment E35) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is a 5- or 6- membered heteroaryl containing one or two heteroatoms selected from N, S, and O, optionally substituted with one to three substituents, independently selected from halogen, hydroxy,–O-C₁- ^C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, -C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), and–S(=O)_k–R⁵, and all other variables are as defined in Embodiment E1.

A thirty-sixth embodiment (Embodiment E36) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is halogen, and all other variables are as defined in Embodiment E1.

A thirty-seventh embodiment (Embodiment E37) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is -CN, and all other variables are as defined in Embodiment E1.

A thirty-eighth embodiment (Embodiment E38) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is –O-C₁-C₆ alkyl, optionally substituted with one to three substituents, independently selected ^{from halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, -C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), and– S(=O)_k–R⁵, and all other variables are as defined in Embodiment E1.

A thirty-ninth embodiment (Embodiment E39) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–C₁-C₆ alkyl, optionally substituted with one to three substituents, independently selected from halogen, ^{hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, -C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), and–S(=O)_k–R⁵, and all other variables are as defined in Embodiment E1.

A fortieth embodiment (Embodiment E40) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–C₂-C₆ alkenyl, optionally substituted with one to three substituents, independently selected from ^{halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, -C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), and–S(=O)_k– R5, and all other variables are as defined in Embodiment E1.

A forty-first embodiment (Embodiment E41) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–S(=O)_k– R², and all other variables are as defined in Embodiment E1. A forty-second embodiment (Embodiment E42) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is –(C(O)O)_m N(R^3A)(R^3B), and all other variables are as defined in Embodiment E1.

A forty-third embodiment (Embodiment E43) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–OH, and all other variables are as defined in Embodiment E1.

A forty-fourth embodiment (Embodiment E44) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–oxo, and all other variables are as defined in Embodiment E1.

A forty-fifth embodiment (Embodiment E45) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–C(=O)- (O)_m–R⁴, and all other variables are as defined in Embodiment E1.

A forty-sixth embodiment (Embodiment E46) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is–Cl, and all other variables are as defined in Embodiment E1.

A forty-seventh embodiment (Embodiment E47) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is –OCH₃, and all other variables are as defined in Embodiment E1.

A forty-eighth embodiment (Embodiment E48) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2- E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9- E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in any of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is –SCH₃, and all other variables are as defined in Embodiment E1.

A forty-ninth embodiment (Embodiment E49) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is as defined in any of Embodiments E2-E3, Y is as defined in any of Embodiments E4-E8, n is as defined in any of Embodiments E9-E11, one or more occurrences of X is as defined in any of Embodiments E12-E18, R⁷ is as defined in an of Embodiments E19-E26, Z is as defined in any of Embodiments E27-E32, R¹ is

,

and all other variables are as defined in Embodiment E1.

E50) is a compound of Formula (IA) or (IB),

,

or a pharmaceutically acceptable salt thereof, wherein, Z is CH or N; and R¹ is selected from the group consisting of:

(a) hydrogen,

(b) a 6-membered aryl,

(d) halogen, ^(e)–O-C ₁ ^-C ₆ ^alkyl,

(^f)–C ₁ ^-C ₆ ^{alkyl, and}

(g)–S(=O)_k–R²,

w^{herein said 6-membered aryl, 5- or 6-membered heteroaryl,–O-C} ₁ ^-C ₆ ^{alkyl, and–C} ₁ ^-C ₆ ^alkyl are optionally substituted as defined in the Summary of the Invention; and all other variables are as defined in Embodiment E1.

A fifty-first embodiment (Embodiment E51), is a compound of Formula (I), selected from the group consisting of:

6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycycloheptyl) benzo[h]quinazolin-4(3H)- one;

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-methylpyridin-3-yl)methyl)benzo[h] quinazolin-4(3H)- one;

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)benzo[h]quinazolin-4(3H)-one;

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-methoxypyridin-3-yl)methyl)benzo [h]quinazolin- 4(3H)-one;

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-(methylthio)pyridin-3-yl)methyl)benzo[h]quinazolin- 4(3H)-one;

Benzyl 4-(6-((6-chloropyridin-3-yl)methyl)-4-oxopyrido[3,2-h]quinazolin-3(4H)-yl)-3- hydroxyazepane-1-carboxylate;

6-((6-chloropyridin-3-yl)methyl)-3-(3-hydroxyazepan-4-yl)pyrido[3,2-h]quinazolin-4(3H)-one; Benzyl 3-hydroxy-4-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxopyrido[3,2- h]quinazolin-3(4H)-yl)azepane-1-carboxylate; and

3-(3-hydroxyazepan-4-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)pyrido[3,2- h]quinazolin-4(3H)-one,

or a pharmaceutically acceptable salt thereof.

Reference to compounds of the present invention specifically includes different embodiments of Formula (I) such as Formula (IA) and Formula (IB), sub-embodiments of Formula (IA) and Formula (IB), other embodiments provided herein, individual compounds described herein and their pharmaceutically acceptable salts.

Other specific embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula (I), (IA), or (IB), as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a second compound, wherein the second compound is useful for the treatment of Alzheimer’s disease, schizophrenia, pain, cognitive impairment, or sleep disorders.

(c) The pharmaceutical composition of (a), further comprising a second compound, wherein the second compound is useful for treating, preventing, controlling, ameliorating, or reducing the risk of side effects or toxicity of the compounds of the invention.

(d) A pharmaceutical composition comprising (i) a compound of Formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, and (ii) a second compound, wherein the second compound is useful for the treatment of Alzheimer’s disease, schizophrenia, pain or sleep disorders, wherein the compound of Formula (I), (IA), or (IB) (or a pharmaceutically acceptable salt thereof), and the second compound are each employed in an amount that renders the combination effective for treating Alzheimer’s disease, schizophrenia, pain, cognitive impairment, or sleep disorders.

(e) A method for treating a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of

Alzheimer’s disease, schizophrenia, pain, cognitive impairment, and sleep disorders, in a patient which comprises administering to a patient in need of such treatment an effective amount of a compound of Formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof.

(f) A method for treating Alzheimer’s disease which comprises administering to a subject in need of such treatment an effective amount of a compound of Formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof.

(g) A method for treating schizophrenia which comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of (a), (b), (c) or (d).

The present invention also includes a compound of Formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation (or manufacture) of a medicament for, medicine or treating diseases or disorders mediated by the muscarinic M1 receptor, e.g. Alzheimer’s disease, schizophrenia, cognitive impairment, pain, or sleep disorders. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents as discussed herein.

Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(g) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments, classes or sub-classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.

In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (g) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.

Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula (I), (IA), or (IB) or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula (I), (IA), or (IB) or its salt per se; i.e., the purity of the active ingredient in the composition. Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc... As used throughout the specification and in the appended claims, the singular forms“a,”“an,” and“the” include the plural reference unless the context clearly dictates otherwise.

As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

A“patient” is generally a human being, male or female, in whom M1 allosteric modulation is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.

The term "effective amount" or“pharmaceutically effective amount” as used herein, refers to an amount of a compound of the invention and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect, e.g. treatment of Alzheimer’s Disease, cognitive disorders, schizophrenia, pain disorders and/or sleep disorders when administered to a patient. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents

administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

As used herein, the term "treatment" or "treating" means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).

The term "alkyl,” as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C₁-C₆ alkyl) or from about 1 to about 4 carbon atoms (C₁-C₄ alkyl). Non- limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

Unless otherwise indicated, an alkyl group is unsubstituted.

The term "alkenyl,” as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl. The term“C₂-C₆ alkenyl” refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.

The term“alkylene,” as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group’s hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include–CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, - CH(CH₃)CH₂CH₂-, -CH(CH₃)- and -CH₂CH(CH₃)CH₂-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is - CH₂-. The term“C₁-C₆ alkylene” refers to an alkylene group having from 1 to 6 carbon atoms.

The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.

The term "cycloalkyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. In one embodiment, a cycloalkyl group is unsubstituted. The term“3 to 6- membered cycloalkyl” refers to a cycloalkyl group having from 3 to 6 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a“cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:

.

The term“halogen,” as used herein, means–F, -Cl, -Br or -I.

The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include–CH₂F, -CHF₂, -CF₃, -CH₂Cl and -CCl₃. The term“C₁-C₆ haloalkyl” refers to a haloalkyl group having from 1 to 6 carbon atoms.

The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with an–OH group. In one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include–CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH and - CH₂CH(OH)CH₃. The term“C₁-C₆ hydroxyalkyl” refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.

The term“heteroaryl,” as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic and had 9 or 10 ring atoms. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term“heteroaryl” also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term“heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.

"Heterocycle" or a“heterocyclic ring” means a monocyclic or bicyclic saturated, partially unsaturated, or unsaturated ring system containing 5-10 atoms and containing at least one ring heteroatom selected from N, S and O. In select embodiments, the ring system contains 1-4 heteroatoms selected from N, S and O. When a heterocycle contains two rings, the rings may be fused, bridged or spirocyclic. Examples of monocyclic heterocycle rings include piperazine, piperidine, and morpholine. Examples of bicyclic heterocycle rings include 1,4- diazabicyclo[2,2,2]octane and 2,6-diazaspiroheptane.

The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, or N, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any–NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term “heterocycloalkyl” also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, and the like, and all isomers thereof.

A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is:

.

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl. The term“3 to 6-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms. The term“4 to 6-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 6 ring atoms. The term“7 to 11-membered bicyclic heterocycloalkyl” refers to a bicyclic

heterocycloalkyl group having from 7 to 11 ring atoms.

The term“substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By“stable compound” or“stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Unless otherwise stated, as employed herein, when a moiety (e.g., cycloalkyl, aryl, alkyl, heteroaryl, heterocyclic, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.

The term“substantially pure” as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "substantially pure” also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed“protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any substituent or variable (e.g., alkyl, R^6A, R^6B, R⁷, etc.) occurs more than one time in any constituent or in Formula (I), (IA), or (IB), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

Combinations of substituents and/or variable are permissible only if such combination results in a stable compound.

As used herein, the term“composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

The compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term“unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

The compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. When treating or ameliorating a disorder or disease for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. The total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material. Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and

Pergamon Press. The term“prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to provide a compound of the invention or a pharmaceutically acceptable salt or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.

For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C₁–C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 6 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β- dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl- 1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁- C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkyl, α-amino(C₁-

arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α- aminoacyl group is independently selected from the naturally occurring L-amino acids, - P(O)(OH)₂, -P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR’-carbonyl- wherein R and R’ are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, a natural α-aminoacyl, - C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, -C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl; carboxy (C₁-C₆)alkyl; amino(C₁-C₄)alkyl or mono-N- or di-N,N-(C₁- C₆)alkylaminoalkyl; -C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N-(C₁- C₆)alkylamino morpholino; piperidin-1-yl or pyrrolidin-1-yl, and the like.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, C_1-4alkyl, -O-(C_1-4alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C_1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C_6-24)acyl glycerol.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non- limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of isolatable solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS

PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The compounds of the invention can form salts which are also within the scope of this invention. Reference to a compound of the invention, e.g. a compound of Formula (I), (IA), or (IB), is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds disclosed herein may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.

Additionally, acids which are generally considered suitable for the formation of

pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.

It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

Stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt,”“solvate,”“ester,”“prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, or racemates of the inventive compounds. In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula (I), (IA), and (IB). For example, different isotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. In one embodiment, a Compound of Formula (I), (IA), and (IB) has one or more of its hydrogen atoms replaced with deuterium.

Polymorphic forms of the compounds of the invention, and of the salts, solvates, hydrates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention.

As used herein, the term "muscarinic M1 receptor " refers to one of the five subtypes of the muscarinic acetylcholine receptor, which is from the superfamily of G-protein coupled receptors. The family of muscarinic receptors is described, for example, in Pharmacol Ther, 1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002, 61:1297-1302. The muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites. See, e.g., S. Lazareno et al, Mol Pharmacol, 2002, 62:6, 1491-1505.

As used herein, the terms“positive allosteric modulator” and“allosteric potentiator” are used interchangeably, and refer to a ligand which interacts with an allosteric site of a receptor to activate the primary binding site. The compounds of the invention are positive allosteric modulators of the muscarinic M1 receptor. For example, a modulator or potentiator may directly or indirectly augment the response produced by the endogenous ligand (such as acetylcholine or xanomeline) at the orthosteric site of the muscarinic M1 receptor in an animal, in particular, a human.

The actions of ligands at allosteric receptor sites may also be understood according to the“allosteric ternary complex model,” as known by those skilled in the art. The allosteric ternary complex model is described with respect to the family of muscarinic receptors in Birdsall et al, Life Sciences, 2001, 68:2517-2524. For a general description of the role of allosteric binding sites, see Christopoulos, Nature Reviews: Drug Discovery, 2002, 1:198-210.

While not wishing to be bound by theory, it is believed that the compounds of the invention bind to an allosteric binding site that is distinct from the orthosteric acetylcholine site of the muscarinic M1 receptor, thereby augmenting the response produced by the endogenous ligand acetylcholine at the orthosteric site of the M1 receptor. It is also believed that the compounds of the invention bind to an allosteric site which is distinct from the xanomeline site of the muscarinic M1 receptor, thereby augmenting the response produced by the endogenous ligand xanomeline at the orthosteric site of the M1 receptor. The following abbreviations are used throughout the text and have the following meanings: Aq = aqueous; m-CPBA = meta-chloroperoxybenzoic acid; BIPPYPHOS = 5-(Di- tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; BOC = tert-butyloxycarbonyl; BOP = Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; t- BuOH = tert-butyl alcohol; Con HCL = concentrated hydrochloric acid; DCM =

dichloromethane; DIPEA = N,N-Diisopropylethylamine; DMEM = Dulbecco’s Modified Eagle Medium (High Glucose); DMA = Dimethylacetamide; DMF = N,N-dimethylformamide;

DMFDMA= N,N-dimethylformamide dimethylacetal; DMSO = dimethylsulfoxide; FBS = fetal bovine serum; FLIPR = Fluorometric Imaging Plate Reader System; h = hours; HATU = O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HPLC = high performance liquid chromatography; LRMS= low resolution mass spectometry; Me = methyl; MeOH = methanol; NMR = nuclear magnetic resonance; Pd/C= palladium on carbon; Pd₂(dba)₃ = tris(dibenzylideneacetone) dipalladium; RT = room temperature; TEA = trimethylamine; and THF= tetrahydrofuran. Methods of Use of the Compounds of Formula (I):

The present invention is directed to the use of the compounds of Formula (I), (IA) or (IB), disclosed herein as M1 allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound. In addition to humans, a variety of other mammals can be treated according to the method of the present invention. The compounds of the present invention have utility in treating or ameliorating Alzheimer’s disease. The compounds may also be useful in treating or ameliorating other diseases mediated by the muscarinic M1 receptor, such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment). Other conditions that may be treated by the compounds of the invention include Parkinson’s Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention are useful in treating Alzheimer’s Disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be useful for the prevention of dementia of the Alzheimer’s type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer’s type.

Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful include one or more of the following conditions or diseases:

schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketanine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline. Thus, in another specific embodiment, the present invention provides a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.. At present, the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American

Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. As used herein, the term "schizophrenia or psychosis" includes treatment of those mental disorders as described in DSM-IV-TR. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term "schizophrenia or psychosis" is intended to include like disorders that are described in other diagnostic sources.

Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity;

decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep;

reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy;

interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruptions; jet- lag; shift workers' sleep disturbances; dyssomnias; night terror; insomnias associated with depression, emotional/mood disorders, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules; conditions due to drugs which cause reductions in REM sleep as a side effect; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; and conditions which result from a diminished quality of sleep. Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic

mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (e.g., postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout), headache, migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.

Compounds of the invention may also be used to treat or prevent dyskinesias. Furthermore, compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g., alcohol, opioids, and cocaine.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor,

contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.

Examples of combinations of the compounds of the present invention include combinations with anti-Alzheimer's Disease agents, for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretase inhibitors, such as LY450139 and TAK 070; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR β agonists; ApoE4 conformational modulators; NR2B antagonists; androgen receptor modulators; blockers of Aβ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists, such as lecozotan; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACC001, CAD106, AZD3102, H12A11V1; anti-inflammatory compounds such as (R)-flurbiprofen,

nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists, such as AVE1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089;

growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H₃ receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP16795; AMPA agonists or AMPA modulators, such as CX-717, LY 451395, LY404187 and S-18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABA_A inverse agonists; GSK3β inhibitors, including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective M1 agonists; HDAC inhibitors; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.

Examples of combinations of the compounds include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines,

pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, aiprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproelone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine,

fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride,

acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride,

tetrabenazine, frihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

Examples of combinations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such as AMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin B l receptor antagonists, such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such as

AZD4282; potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA- A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase Bl5 ("MAO- B") inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as AZD4282; NKI antagonists; selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), such as duloxetine; tricyclic antidepressant drugs, norepinephrine modulators;

lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the present invention may be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. Having described different embodiments of the invention herein with reference to the accompanying drawings, it is to be understood that the invention is not limited to those precise embodiments, and that various changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing methodologies and materials that might be used in connection with the present invention.

All reactions were stirred (mechanically, stir bar/stir plate, or shaken) and conducted under an inert atmosphere of nitrogen or argon unless specifically stated otherwise and all solvents were anhydrous unless otherwise specified. The progress of reactions was determined by either analytical thin layer chromatography (TLC) performed with E. Merck (EMD Millipore, Billerica MA) pre-coated TLC plates, silica gel 60E-254, layer thickness 0.25 mm or liquid chromatography-mass spectrum (LC-MS). Mass analysis was performed on an Agilent 1200Series coupled with Agilent 6130 Quadrupole LC\MS with ES+APCI

(positive/negative) mode. High performance liquid chromatography (HPLC) was conducted on an Agilent 1200 series HPLC on ATLANTIS dCl8(250x4.6m -511) column with gradient 10:90-100 v/vCH3CN/H20 + v 0.1 % TFA in water; flow rate 10 mL/min, UV wavelength 215nm). Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was performed by Biotage-Isolera TM Flash chromatography instrument on Biotage® SNAP KP-Sil pre-packed with 50 Pm silica particles with a surface area of 500 m²/g. 1H-NMR spectra were obtained on a 400 BRUKER Avance ® Spectrometer in CDCI3 or CD3OD or other solvents as indicated and chemical shifts are reported as δ using the solvent peak as reference and coupling constants are reported in hertz (Hz). EXAMPLE 1

Preparation of Compound 1 (C1)

6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycycloheptyl)

benzo[h]quinazolin-4(3H)-one

SCHEME 1 Step 1: Preparation of (E)-N,N-dimethyl-2-(1-nitronaphthalen-2-yl)ethenamine

A solution of 2-methyl-1-nitronaphthalene (10.0 g, 53.4 mmol) and N,N-dimethyl formamide dimethyl acetal (14.3 mL, 107 mmol) in anhydrous DMF (18 mL) was refluxed at 160 ^oC for 48 hours. The mixture was cooled to room temperature and 50 mL of hexanes was added. After vigorously stirring for 30 minutes, a solid was collected, washed with additional hexanes, and dried to provide the title compound. Step 2: Preparation of 1-nitro-2-naphthoic acid

To a solution of (E)-N,N-dimethyl-2-(1-nitronaphthalen-2-yl)ethenamine (5.00 g, 20.6 mmol) and potassium carbonate (6.85 g, 49.5 mmol) in a 1:1 mixture of t-BuOH : H₂O (100 mL) at 0 ^oC was added potassium permanganate (7.83 g, 49.5 mmol) slowly over 20 minutes. The mixture was stirred at room temperature for 4 hours, after which a precipitate was filtered and washed twice with 70 mL water. The filtrate was concentrated to 40 mL in volume and acidified with 6 N HCl to pH ~2. The solid obtained, was filtered, washed with 60 mL of water, and dried to provide the title compound. Step 3: Preparation of methyl 1-nitro-2-naphthoate

To a solution of 1-nitro-2-naphthoic acid (1.80 g, 8.29 mmol) in dichloromethane (20 mL) at 0 ^oC was added DMF (0.032 mL, 0.414 mmol) followed by oxalyl chloride (0.73 mL, 8.3 mmol) drop wise. After 1 hour, the mixture was concentrated in vacuo and then dissolved in MeOH (40 mL) under nitrogen atmosphere. After stirring for 15 hours, the mixture was concentrated in vacuo, diluted with 10% aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with hexanes, filtered and dried in vacuo to provide the title compound. Step 4: Preparation of methyl 1-amino-2-naphthoate To a solution of methyl 1-nitro-2-naphthoate (1.50 g, 6.49 mmol) in methanol (20 mL) and THF (1 mL) was added palladium on carbon (0.276 g, 2.60 mmol). The mixture was sparged under an atmosphere of hydrogen and stirred at ambient temperature for 6 hours. The mixture was filtered, the solids were washed with additional MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (5 - 10 % ethyl acetate in petroleum ether) to provide the title compound. Step 5: Preparation of methyl 1-amino-4-bromo-2-naphthoate

To a stirred solution of methyl 1-amino-2-naphthoate (500 mg, 2.48 mmol) in mixture of 1:1 dioxane : CCl₄ (4 mL) at 0 °C was added a solution of bromine (0.128 mL, 2.485 ^{mmol) in mixture of 1:1 dioxane: CCl} ₄ ^{( 8 mL) drop wise. After stirring at 0°C for 2 hours, the} solid was separated by filtration, washed with hexane repeatedly, and dried in vacuo to provide the title compound; mass ion (ES+) of 281.8 [M+H]⁺ [Calc’d for C₁₂H₁₁BrNO₂ [M+H]⁺= 281.2. Step 6: Preparation of methyl 1-amino-4-((6-chloropyridin-3-yl)methyl)-2-naphthoate

To a solution of methyl 1-amino-4-bromo-2-naphthoate (1.50 g, 5.35 mmol) in tetrahydrofuran (10 mL) at 0 °C was added a solution of (2-chloro-5-pyridyl)methylzinc chloride (32.1 mL, 16.1 mmol), followed by bis(tri-tert-butylphosphino)palladium(0) (0.137 g, 0.268 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours. The reaction mixture was cooled to 0 °C, treated with water (5 mL), and diluted with dichloromethane/water. The resulting solid was filtered through a bed of CELITE and the filtrate was extracted with dichloromethane (2x 30 mL). The combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (10 - 15 % ethyl acetate in petroleum ether) to provide the title compound; mass ion (ES+) of 327.0 [M+H]⁺ [Calc’d for C₁₈H₁₆ClN₂O₂ [M+H]⁺= 327.1]. Step 7: Preparation of 1-amino-4-((6-chloropyridin-3-yl)methyl)-2-naphthoic acid

To a stirred solution of methyl 1-amino-4-((6-chloropyridin-3-yl)methyl)-2- naphthoate (1.00 g, 3.06 mmol) in MeOH (4 mL), tetrahydrofuran (4 mL) and water (1 mL) at 0 °C, was added lithium hydroxide (0.366 g, 15.3 mmol). After stirring at 0 °C for 5 minutes, the mixture was warmed to room temperature and stirred for 24 hours. The mixture was partially concentrated in vacuo and acidified with hydrochloric acid to pH ~3. The resulting solid was collected via filtration, washed twice with water and dried in vacuo to provide the title compound; mass ion (ES+) of 311.0 [M-H]⁺ [Calc’d for C₁₇H₁₂ClN₂O₂ [M-H]⁺= 311.1]. Step 8: Preparation of 1-amino-4-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2-hydroxy cycloheptyl)-2-naphthamide

To a stirred solution of 1-amino-4-((6-chloropyridin-3-yl)methyl)-2-naphthoic acid (500 mg, 1.60 mmol) in DMF (5 mL) at room temperature was added BOP (707 mg, 1.60 mmol), (1S,2S)-2-aminocycloheptanol (248 mg, 1.92 mmol), and TEA (223 μL, 1.60 mmol) respectively. The mixture was stirred for 3 hours at room temperature, treated with cold water, and then extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 30 % ethyl acetate in petroleum ether) to provide the title compound; mass ion (ES+) of 424.4 [M+H]⁺ [Calc’d for C₂₄H₂₇ClN₃O₂ [M]⁺= 424.2. Step 9: Preparation of 6-((6-chloropyridin-3-yl) methyl)-3-((1S,2S)-2-hydroxycycloheptyl) benzo[h]quinazolin-4(3H)-one

A solution of 1-amino-4-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2- hydroxycycloheptyl)-2-naphthamide (500 mg, 1.18 mmol) in N,N-dimethyl formamide dimethyl acetal (1.41 g, 11.8 mmol) was heated at 140 °C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0 - 20 % ethyl acetate in petroleum ether) to provide the title compound (C1); mass ion. LRMS (ES+) of 434.4 [M+H]⁺ [Calc’d for C₂₅H₂₄ClN₃O₂ = 434.2] ¹H NMR (400MHz, DMSO-d₆): δ.8.99 (d, J = 7.8 Hz, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.81-7.74 (m, 2H), 7.67 (dd, J = 8.4, 2.3 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.57 (s, 2H), 4.12 (s, 1H), 2.14 (bs, 1H), 1.91-1.82 (m, 1H), 1.75 - 1.73 (m, 2H), 1.68 - 1.64 (m, 3H), 1.59 - 1.48 (m, 3H) ppm. EXAMPLE 2

Preparation of Compound 2 (C2)

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-methylpyridin-3-yl)methyl)benzo[h]

quinazolin-4(3H)-one (C2)

To a solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycycloheptyl)benzo[h] quinazolin-4(3H)-one (Example 1, 40 mg, 0.092 mmol) in DMF (2 mL) at room temperature under an atmosphere of nitrogen was added

bis(triphenylphosphine)palladium(II)dichloride (1.8 mg, 2.6 μmol) and tetramethyltin (18 mg, 0.10 mmol). The mixture was heated at 110 °C for 24 hours, cooled to room temperature, and treated with water (2mL). The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (0– 50 % ethyl acetate in petroleum ether to provide the title compound; mass ion LRMS (ES+) 414.4 [M+H]⁺ [Calc’d for

C₂₆H₂₈N₃O₂ = 414.1]. ¹H NMR (400MHz, DMSO-d₆): δ 8.99 (dd, J = 8.3, 1.5 Hz, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.80-7.73 (m, 2H), 7.48 (dd, J = 7.9, 2.3 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.51 (s, 2H), 4.12 (s,1H), 2.42 (s, 3H), 1.91-1.83 (m, 1H), 1.82-1.73 (m, 3H), 1.71-1.69 (m, 3H), 1.68-1.54 (m, 3H) ppm. EXAMPLE 3

Preparation of Compound 3 (C3)

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)benzo[h]quinazolin-4(3H)-one (C3)

To a stirred solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycycloheptyl) benzo[h]quinazolin-4(3H)-one (Example 1, 40 mg, 0.092 mmol) in dioxane (2 mL) and water (0.67 ml) under an atmosphere of nitrogen was added Na₂CO₃ (29 mg, 0.28 mmol), 1-methyl-4-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol (36 mg, 0.186 mmol) and tetrakistriphenylphosphine palladium(0) (5.3 mg, 4.6 μmol). The mixture was heated at 120° for 16 hours, cooled to room temperature, and treated with water (2mL). The mixture was extracted twice with ethyl acetate and the combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified via silica gel column

chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound; mass ion LRMS (ES+) 480.4 [M+H] [Calc’d for C₂₉H₃₀N₅O₂ = 480.2].¹H NMR (400MHz, DMSO- d₆): δ 8.98 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.21 (d, J = 9.2 Hz, 2H), 7.93 (d, J = 5.6 Hz, 2H), 7.78-7.74 (m, 2H), 7.56-7.52 (m, 2H), 4.90 (s, 1H), 4.52 (s, 2H), 4.12 (s, 1H), 3.86 (s, 3H), 2.50 (s, 1H), 1.90-1.80 (m, 1H), 1.77-1.74 (m, 2H), 1.72-1.61 (m, 3H), 1.57-1.51 (m, 3H) ppm. EXAMPLE 4

Preparation of Compound 4 (C4)

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-methoxypyridin-3-yl)methyl)benzo

[h]quinazolin-4(3H)-one

To a stirred solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycycloheptyl) benzo[h]quinazolin-4(3H)-one (Example 1, 50 mg, 0.11 mmol) in MeOH (3 mL) under an atmosphere of nitrogen was added potassium hydroxide (9.7 mg, 0.17 mmol), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole (1.2 mg, 2.3 μmol) and tris(dibenzyledeneacetone) dipalladium(0) (0.53 mg, 0.58 μmol). The mixture was heated at 80 °C for 6 hours, cooled to room temperature, and treated with water (2mL). The mixture was extracted twice with dichloromethane and the combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 20 % ethyl acetate in petroleum ether) to provide the title compound; mass ion LRMS (ES+) of 430.2 [M+H] [Calc’d for C₂₆H₂₈N₃O₃ = 430.2]. ¹H NMR (400MHz, DMSO-d₆): δ 8.97 (d, J = 8.0 Hz, 1H), 8.59 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.79-7.72 (m, 2H), 7.53 (dd, J = 8.4, 2.4 Hz, 1H), 4.48 (s, 1H), 3.81 (s, 3H), 2.12-1.91 (m, 1H), 1.89-1.84 (m, 1H), 1.83-1.75 (m, 2H), 1.73-1.62 (m, 4H), 1.60-1.49 (m, 3H) ppm. EXAMPLE 5

Preparation of Compound 5 (C5)

3-((1S,2S)-2-hydroxycycloheptyl)-6-((6-(methylthio)pyridin-3-yl)methyl) benzo[h]quinazolin-4(3H)-one

To a solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycycloheptyl)benzo [h]quinazolin-4(3H)-one (Example 1, 60 mg, 0.14 mmol) in N- methyl-2-pyrrolidinone (1 mL) was added sodium thiomethoxide (48 mg, 0.69 mmol) at room temperature. The vessel was sealed and heated at 90 °C in microwave reactor for 15 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate and water, and extracted thrice with ethyl acetate. The combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound; mass ion LRMS (ES+) 446.4 [M+H] [Calc’d for C₂₆H₂₈N₃O₂S = 446.2].¹H NMR (400MHz, DMSO-d₆): δ 8.99 (d, J = 8.0 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.81-7.73 (m, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 4.50 (s, 2H), 2.48 (s, 3H), 2.19-2.15 (m, 1H), 1.94-1.91 (m, 1H), 1.81-1.73 (m, 3H), 1.68-1.61 (m, 3H) 1.60-1.49 (m, 3H) ppm. EXAMPLE 6

Preparation of Compound 6 (C6)

Benzyl 4-(6-((6-chloropyridin-3-yl)methyl)-4-oxopyrido[3,2-h]quinazolin-3(4H)-yl)-3- hydroxyazepane-1-carboxylate

SCHEME 2

Step 1: Preparation of benzyl allylcarbamate

To a stirred solution of prop-2-en-1-amine (1.00 g, 17.5 mmol) and sodium bicarbonate (2.94 g, 35.0 mmol) in a mixture of ethanol (10 mL) and water (10 mL) at 0 °C was added benzyl chloroformate (3.29 g, 19.3 mmol) dropwise over 1 hour. The mixture was stirred for 1 hour at 0 °C and then an additional 12 hours at ambient temperature. The mixture was diluted with water (20 mL), concentrated in vacuo to ~30 mL and then extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound. Step 2: Preparation of benzyl allyl(pent-4-en-1-yl)carbamate

To a suspension of sodium hydride (0.627 g, 15.7 mmol) in DMF (10 mL) was added benzyl allylcarbamate (1.50 g, 7.84 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 10 minutes after which 5-bromo-1-pentene (1.753 g, 11.77 mmol) was added dropwise. The mixture was heated at 40 °C for 4 hours, cooled to ambient temperature, and then treated with ice water. The mixture was partitioned between dichloromethane and water and the organic extract was washed with water and brine, dried with Na₂SO₄, filtered and concentrated in vacuo to provide the title compound. LRMS (ES+) 260.2 [M+H] [Calc’d for C ⁺

1₆H₂₂NO₂ [M+H] = 260.2] Step 3: Preparation of benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

To a degassed solution of benzyl allyl(pent-4-en-1-yl)carbamate (1.00 g, 3.86 mmol) in dichloromethane (10 mL) was added Grubbs catalyst 2^nd generation (0.131 g, 0.154 mmol). The mixture was refluxed for 3 hours, cooled to ambient temperature, and concentrated in vacuo. The residue was purified by silica gel column chromatography (45 - 50 %

dichloromethane in petroleum ether) to provide the title compound; mass ion LRMS (ES+) of 232.2 [M+H] [Calc’d for C₁₄H₁₈NO₂ [M+H]⁺= 232.2.in (0.02 mL), stirred for 1 hour, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 10% K₂CO₃ solution (3x25 mL) and brine (25 mL), dried with Na₂SO₄, filtered, concentrated in vacuo to provide the title compound; mass ion (ES+) of 248.4 [M+H] [Calc’d for C₁₄H₁₈NO₃ [M+H]⁺= 248.1] Step 5: Preparation of benzyl 4-amino-3-hydroxyazepane-1-carboxylate and benzyl 3-amino-4- hydroxyazepane-1-carboxylate

To a solution of the benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate (100 mg, 0.404 mmol) in MeOH (1 mL) was added ammonium hydroxide (2.00 mL, 57.1 mmol). The mixture was heated to 80 °C in a sealed tube for 16 hours, cooled to ambient temperature, and concentrated in vacuo to provide the title compounds as a mixture; mass ion (ES+) of 265.4 [M+H] [Calc’d for C₁₄H₂₁N₂O₂ [M+H]⁺= 265.2] Step 6: Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxyazepane-1-carboxylate and benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxyazepane-1-carboxylate

To a stirred solution of benzyl 4-amino-3-hydroxyazepane-1-carboxylate and benzyl 3-amino-4-hydroxyazepane-1-carboxylate (100 mg, 0.378 mmol) in dichloromethane (4 mL) at room temperature was added triethylamine (0.052 mL, 0.378 mmol) and di-tert-butyl dicarbonate (0.082 mL, 0.378 mmol). The mixture was stirred at room temperature for 3 hours, treated with water (10 mL), and extracted with dichloromethane (2x10 mL). The combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The regioisomers were purified by preparative reverse phase HPLC (90:10 to 0:100; water containing 0.1% formic acid : acetonitrile containing 0.1% formic acid) to provide the title compounds with benzyl 4- ((tert-butoxycarbonyl)amino)-3-hydroxyazepane-1-carboxylate as the major regioisomer and benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxyazepane-1-carboxylate as minor regioisomer; mass ion (ES+) of 265.2 [M+H-Boc] [Calc’d for C₁₉H₂₈N₂O₅ [M]⁺= 364.2] Step 7: Preparation of benzyl 4-amino-3-hydroxyazepane-1-carboxylate

To a stirred solution of benzyl 4-((tert-butoxycarbonyl)amino)-3- hydroxyazepane-1-carboxylate (500 mg, 1.37 mmol) in dichloromethane (8 mL) at 0 °C was added 4.5M HCl in dioxane (0.113 mL, 1.37 mmol). The mixture was stirred for 3 hours at room temperature and then concentrated in vacuo methanol (15 mL) to provide the title compound; mass ion (ES+) of 265.4 [M+H]⁺ [Calc’d for C₁₄H₂₁N₂O₃ [M+H]⁺= 265.1]. Step 8: Preparation of 8-amino-5-((6-chloropyridin-3-yl)methyl)quinoline-7-carboxylic acid

Utilizing the general procedures described in Example 1, substituting 7-methyl-8- nitroquinoline for 2-methyl-1-nitronaphthalene, the title compound was prepared. Step 9: Preparation of benzyl 4-(8-amino-5-((6-chloropyridin-3-yl)methyl)quinoline-7- carboxamido)-3-hydroxyazepane-1-carboxylate

To a stirred solution of 8-amino-5-((6-chloropyridin-3-yl)methyl)quinoline-7- carboxylic acid (300 mg, 0.956 mmol) in a DMF (5 mL) at room temperature was added BOP (634 mg, 1.43 mmol), benzyl 4-amino-3-hydroxyazepane-1-carboxylate (379 mg, 1.43 mmol) and TEA (0.400 mL, 2.87 mmol). The mixture was stirred for 3 hours at room temperature, treated with cold water, and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (45 - 50 % ethyl acetate in petroleum ether) to provide the title compound; mass ion (ES+) of 561.0 [M+H]⁺ [Calc’d for C₃₀H₃₁ClN₅O₄ [M+H]⁺= 561.2]. Step 10: Preparation of 4-(6-((6-chloropyridin-3-yl)methyl)-4-oxopyrido[3,2-h]quinazolin- 3(4H)-yl)-3-hydroxyazepane-1-carboxylate

To a solution of benzyl 4-(8-amino-5-((6-chloropyridin-3-yl)methyl)quinoline-7- carboxamido)-3-hydroxyazepane-1-carboxylate (300 mg, 0.536 mmol) in DMF (3 mL) was added N,N-dimethylformamide dimethylacetal (3.00 mL, 22.4 mmol) at room temperature. The mixture was heated at 80 °C for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (90:10 to 0:100; water containing 0.1% formic acid: acetonitrile containing 0.1% formic acid) to provide the title compound; mass ion LRMS (ES+) of 571.2 [M+H]⁺ [Calc’d for C₃₁H₃₀ClN₅O₄ = 571.2]. ¹H NMR (400MHz, CD₃OD): δ 9.10– 9.09 (m, 1H), 8.62 (dd, J =8.5, 1.4 Hz, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.79– 7.78 (m, 1H), 7.68 (dd, J = 8.3, 1.4, Hz, 1H), 7.42– 7.41 (m, 6H), 5.24 (s, 2H), 4.62 (s, 2H), 4.60– 4.54 (m, 1H), 3.83– 3.82 (m, 1H), 3.77– 3.76 (m, 2H), 3.62– 3.55 (m, 1H), 2.75– 2.72 (m, 1H), 2.58– 2.50 (m, 1 H), 2.26– 2.25 (m, 2H), 1.96– 1.93 (m, 1H) ppm. EXAMPLE 7

Preparation of Compound 7 (C7)

6-((6-chloropyridin-3-yl)methyl)-3-(3-hydroxyazepan-4-yl)pyrido[3,2-h]quinazolin-4(3H)-one

To a flask containing benzyl 4-(6-((6-chloropyridin-3-yl)methyl)-4- oxopyrido[3,2-h]quinazolin-3(4H)-yl)-3-hydroxyazepane-1-carboxylate (Example 6, 40 mg, 0.070 mmol) was added concentrated HCl (1 mL, 12.18 mmol). The mixture was stirred for 16 hours at room temperature and then concentrated in vacuo with toluene. The residue was purified by preparative reverse phase HPLC (90:10 to 0:100; water containing 0.1% formic acid :

acetonitrile containing 0.1% formic acid) to provide the title compound; mass ion LRMS (ES+) of 436.2 [M+H] [Calc’d for C₂₃H₂₃ClN₅O₂ = 436.2].¹H NMR (400MHz, CD₃OD): δ 9.13– 9.12 (m, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.84– 7.83 (m, 1H), 7.70 (dd, J =8.2, 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.64 (s, 2H), 4.50– 4.48 (m, 2H), 3.65– 3.63 (m, 1H), 3.52– 3.50 (m, 2H), 2.80– 2.78 (m, 1H), 2.36– 2.35 (m, 2H), 2.15– 2.13 (m, 1 H) ppm. EXAMPLE 8

Preparation of Compound 8 (C8)

Benzyl 3-hydroxy-4-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxopyrido[3,2- h]quinazolin-3(4H)-yl)azepane-1-carboxylate

To a stirred solution of benzyl 4-(6-((6-chloropyridin-3-yl)methyl)-4- oxopyrido[3,2-h]quinazolin-3(4H)-yl)-3-hydroxyazepane-1-carboxylate (Example 6, 100 mg, 0.175 mmol) in dioxane (2 mL) and water (0.5 ml) under an atmosphere of nitrogen was added Na₂CO₃ (55.8 mg, 0.526 mmol), 1-methyl-4-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-1H- pyrazol (40.2 mg, 0.193 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.02 mg, 1.75 μmol). The mixture was heated at 110 °C for 1 hour, cooled to room temperature, and treated with water (4 mL). The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 8 % methanol in dichloromethane) to provide the title compound that gave a mass ion (ES+) of 616.2 [M+H] [Calc’d for C₃₅H₃₄N₇O₄ = 616.3]. ¹H NMR (400MHz, CD₃OD): δ 9.09– 9.08 (m, 1H), 8.66– 8.64 (m, 1H), 8.51– 8.50 (m, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.78– 7.77 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.41– 7.40 (m, 5H), 5.19 (s, 2H), 4.61 (s, 2H), 4.38– 4.35 (m, 1H), 3.94 (s, 3H), 3.82– 3.81 (m, 2H), 3.66– 3.64 (m, 1H), 3.50– 3.46 (m, 1H), 3.37– 3.36 (m, 1H), 2.55– 2.54 (m, 1H), 2.23– 2.19 (m, 2 H), 2.00– 1.96 (m, 1H) ppm. EXAMPLE 9

Preparation of Compound 9 (C9)

3-(3-hydroxyazepan-4-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)pyrido[3,2- h]quinazolin-4(3H)-one

To flask containing benzyl 3-hydroxy-4-(6-((6-(1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)-4-oxopyrido[3,2-h]quinazolin-3(4H)-yl)azepane-1-carboxylate (Example 8, 80 mg, 0.13 mmol) was added concentrated HCl (12N aqueous, 2 mL). The mixture was stirred for 16 hours at room temperature and then concentrated with toluene. The residue was purified by preparative reverse phase HPLC (90:10 to 0:100; water containing 0.1% formic acid: acetonitrile containing 0.1% formic acid) to provide the title compound; mass ion LRMS (ES+) of 482.2 [M+H] [Calc’d for C₂₇H₂₈N₇O₂ = 482.2]. ¹H NMR (400MHz, CD₃OD): δ 9.17– 9.16 (m, 1H), 8.81 (d, J = 8.7 Hz, 1H), 8.55 (d, J = 7.6 Hz, 2H), 8.32 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 8.07– 8.05 (m, 1H), 7.94– 7.93 (m, 2H), 4.79 (s, 2H), 4.49– 4.48 (m, 2H), 4.00 (s, 3H), 3.64– 3.62 (m, 1H), 3.55– 3.53 (m, 1H), 3.42– 3.38 (m, 1H), 2.84– 2.83 (m, 2H), 2.39– 2.37 (m, 2H), 2.33– 2.28 (m, 1 H) ppm. M1 Receptor Positive Allosteric Modulator Activity Assay

The utility of the compounds as M1 receptor positive allosteric modulators may be demonstrated by methodology known in the art, including by the assay described below. The assay is designed to select compounds that possess modulator activity at the acetylcholine muscarinic M1 receptor or other muscarinic receptors expressed in CHO-NFAT cells by measuring the intracellular calcium with a FLIPR³⁸⁴ Fluorometric Imaging Plate Reader System. The assay studies the effect of one or several concentrations of test compounds on basal or acetylcholine-stimulated Ca²⁺ levels using FLIPR.

Compounds were prepared and subjected to a pre-incubation period of 4 minutes. Thereafter, a single EC₂₀ concentration of acetylcholine was added to each well (3 nM final). The intracellular Ca²⁺ level of each sample was measured and compared to an acetylcholine control to determine any modulatory activity.

Cells: CHO-NFAT/hM1, hM2, hM3 or hM4 cells were plated 24 hours before the assay at a density of 18,000 cells/well (100 μL) in a 384 well plate. CHO-NFAT/hM1 and CHO- NFAT/hM3 Growth Medium: 90% DMEM (Hi Glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and 1mg/ml Geneticin, were added. For M2Gqi5CHO-NFAT and M4Gqi5CHO-NFAT cells, an additional 600 μg/ml hygromycin was added.

Equipment: 384 well plate, 120 μL addition plate; 96-well Whatman 2 ml Uniplate Incubator, 37 °C, 5% CO₂; Skatron EMBLA-384 Plate Washer; Multimek Pipetting System; Genesis Freedom 200 System; Mosquito System; Temo Nanolitre Pipetting System; and FLIPR³⁸⁴ Fluorometric Imaging Plate Reader System are used.

Buffers: Assay Buffer: Hanks Balanced Salt Solution, with 20 mM Hepes, 2.5 mM Probenecid (Sigma P-8761) first dissolved in 1 N NaOH, 1% Bovine Serum Albumin (Sigma A-9647). Dye Loading Buffer: Assay Buffer plus 1% Fetal Bovine Serum and Fluo- 4AM/Pluronic Acid Mixture. 2 mM Fluo-4AM ester stock in DMSO (Molecular Probes F- 14202) Concentration of 2 PM in buffer for a final concentration of 1μM in Assay. 20%

Pluronic Acid Solution stock, with concentration of 0.04% in Buffer, 0.02% in Assay.

65 μL of 2 mM Fluo-4AM were mixed with 130 μL of 20% Pluronic Acid. The resulting solution and 650 μL FBS were added to the assay buffer for a total volume of 65 mL. Positive Controls: 4-Br-A23187: 10 mM in DMSO; final concentration 10 μM. Acetylcholine: 10 mM in water, working stock at both 20 PM and 30 PM in assay buffer, final concentration of 10 μM, which was used to check the maximum stimulation of the CHOK1/hM1 cells. 20 PM (2x) acetylcholine was added in the preincubation part of the assay, and the 30 PM (3x) stock was added in the second part. (EC₂₀)Acetylcholine: 10 mM in water, working stock of 9 nM (3x), and final concentration in assay was 3 nM, which was used after the preincubation with test compounds. Addition of the EC₂₀ Acetylcholine to each well with a test compound was utilized to ascertain any modulator activity. 24 wells contained 3nM Acetylcholine alone as a control. Determining Activity of Putative Compounds:

Screening Plate: Compounds were titrated in 96-well plates (columns 2-11), 100% DMSO, started at a concentration of 15 mM (150x stock concentration), and 3-fold serial dilutions using Genesis Freedom200 System. Four 96-well plates were combined into a 384- well plate using Mosquito Nanolitre Pipetting System by transferring 1Pl of serially diluted compounds to each well, and 1 mM acetylcholine (100x stock concentration) were added as a control. Using Temo, 49 μl assay buffer was added to each well of the 384-well plate right before assay.

In a 96-well Whatman 2ml Uniplate, 9 nM Acetylcholine (3x) is pipetted into wells corresponding to the screening compounds, and into control wells. The 30 PM

acetylcholine control (3x) was added into control wells, and the 3x agonist plate was transferred into a 384 well plate.

Cells were washed three times with 100 μL of buffer, leaving 30μL of buffer in each well. Using Multimek, 30 μL of Dye Loading Buffer was added into each well and incubated at 37°C, 5% CO₂ for up to one hour.G

After 60 minutes, the cells were washed three times with 100 μL of buffer, leaving 30 μL of buffer in each well. The cell plate, screening plate, and agonist addition plates were placed on the platform in the FLIPR and the door closed. A signal test to check background fluorescence and basal fluorescence signal was performed. Laser intensity was adjusted if necessary.

4 minutes of pre-incubation with the test compounds was provided to determine any agonist activity on the M1 receptor by comparison to the 1 mM acetylcholine control. After pre-incubation, the EC₂₀ value of acetylcholine (3 nM final) was added to determine any modulator activity.

A further description of the muscarinic FLIPR assay can be found in International Application Publication No. WO 2004/073639.

In particular, some of the compounds of the following examples had activity in the aforementioned assay. The inflection point is calculated from the FLIPR values, and is a measure of activity. Such a result is indicative of the intrinsic activity of the compounds in use as M1 allosteric modulators.

IP values from the aforementioned assay for representative exemplary compounds of the invention (as described herein) are provided below (Table 1). Table 1. FLIPR Assay Data

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein: each occurrence of X is CR^6AR^6B, or alternatively, up to two occurrences of X are C=O, O, S or NR⁶ and the other occurrences of X, when present, are CR^6AR^6B; each occurrence of Y is CR^6AR^6B; each occurrence of R^6Aand R^6B are independently selected from hydrogen, fluorine,–O-C₁-C₆ ^{alkyl, and -C} ₁ ^-C ₆ ^{alkyl, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and -C} ₁ ^-C ₆ ^{alkyl, are optionally substituted} with one to four substituents independently selected from fluorine,–C₁-C₆ alkyl, and–OC₁-C₆ alkyl; Q is CH or N; R⁶ is hydrogen, halogen,–OH,–O-C₁-C₆alkyl, -C₁-C₆alkyl,–S(=O)_k-R²,–C₂-C₆alkenyl,–CN, - C(=O)-(O)_m-R⁴,–N(R^3A)(R^3B), -C₆-C₁₀aryl, -C₅-C₁₀heteroaryl, -C₅-C₁₀heterocycloalkyl, or - OC(=O)-R⁴, wherein said–O-C₁-C₆alkyl, -C₁-C₆alkyl,–C₂-C₆alkenyl, -C₆-C₁₀aryl, -C₅- C₁₀heteroaryl and -C₅-C₁₀heterocycloalkyl are optionally substituted with one to four substituents independently selected from halogen,–C₁-C₆alkyl, and–OC₁-C₆alkyl; each occurrence of Z is independently CR⁸ or N; each occurrence of R⁷ and R⁸ are independently hydrogen or halogen; R¹ is selected from the group consisting of:

(a) hydrogen,

(b) a 6-membered aryl,

(d) halogen,

(e)–CN,

(f)–O-C₁-C₆alkyl,

(g)–C₁-C₆alkyl,

(h)–C₂-C₆alkenyl,

(i)–S(=O)_k–R²,

(j)–(C(O)O)_mN(R^3A)(R^3B),

(k)–OH,

(l) =O, and

(m) -C(=O)-(O)_m–R⁴,

wherein said 6-membered aryl, 5- or 6-membered heteroaryl,–O-C₁-C₆alkyl,–C₁-C₆alkyl and– C₂-C₆alkenyl are optionally substituted with one to three substituents, independently selected from halogen,–OH,–O-C₁-C₆alkyl,–C₁-C₆alkyl, -C(=O)-(O)_m–R⁴,–N(R^3A)(R^3B), and–S(=O)_k– R⁵; R², R⁴, and R⁵ are independently selected from the group consisting of: hydrogen,–C₁-C₆alkyl,– C₂-C₆alkenyl,–(CH₂)_k-aryl, and–N(R¹)₂, wherein said–C₁-C₆alkyl and–(CH₂)_k-aryl are optionally substituted with up to four halogen,–CN,

wherein said–O-C₁- C₆alkyl is optionally substituted with one to three halogen; R^3A and R^3B are independently selected from the group consisting of:

(1) hydrogen,

(2)–C_1-C₆alkyl,

(3)–C_3-C₆cycloalkyl,

(4)–C(=O)-O- R⁴, and (5)–S(O)₂-R⁴,

or, alternatively, R^3A and R^3B are linked together with the nitrogen to which they are both attached to form a 3- to 6-membered nitrogen-containing heterocyclic ring optionally having one to three additional heteroatoms selected from N, S and O; n is 0, 1 or 2;

k is 0, 1 or 2; and

m is 0 or 1; with the proviso that:

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is CH.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is N.

4. A compound according to any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein both occurrences of Y are CH₂.

5. A compound according to any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein in one occurrence of Y both R^6A and R^6B are hydrogen, and in the other occurrence of Y, R^6A is fluorine and R^6B is fluorine or hydrogen.

6. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and one occurrence of X is–N-C(=O)-(O)_mR⁴.

7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R⁴ is (CH₂)_k-aryl.

8. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and each occurrence of X is–CH₂.

9. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and one occurrence of X is–NH.

10. A compound according to any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein both occurrences of R⁷ are hydrogen.

11. A compound according to any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein at least one occurrence of R⁷ is halogen.

12. A compound according to claim 1, having the structure of Formula IA or IB:

,

or a pharmaceutically acceptable salt thereof, wherein: Z is CH or N; and R¹ is selected from the group consisting of:

(a) hydrogen,

(b) a 6-membered aryl, (c) a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N, S, and O,

(d) halogen,

(e)–O-C₁-C₆alkyl,

(f)–C₁-C₆alkyl, and

(g)–S(=O)_k–R²,

wherein said 6-membered aryl, 5- or 6-membered heteroaryl,–O-C₁-C₆alkyl, and–C₁-C₆alkyl are optionally substituted as defined in claim 1; and all other variables are as defined in claim 1.

13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Z is N.

14. A com ound accordin to claim 1 havin the structure:

or a pharmaceutically acceptable salt thereof.

15. A com ound accordin to claim 1 havin the structure:

, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain and a sleep disorder, said composition comprising a therapeutically effective amount of a compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. Use of a pharmaceutical composition of any of claims 1-15 for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain and sleep disorders.

19. Use of a compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain and sleep disorders.

20. A method of treating a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain and sleep disorders, in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.