WO2017155816A1

WO2017155816A1 - Quinazoline compounds useful as m1 receptor positive allosteric modulators

Info

Publication number: WO2017155816A1
Application number: PCT/US2017/020691
Authority: WO
Inventors: Douglas C. Beshore; Subhendu Kumar MOHANTY; Prashant R. LATTHE; Scott D. Kuduk; Scott B. Hoyt
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2016-03-09
Filing date: 2017-03-03
Publication date: 2017-09-14

Abstract

The present invention is directed to compounds of Formula (I): (Formula (I)) and pharmaceutically acceptable salts thereof, wherein X, Y, Z, R¹, R⁷, R⁸, R⁹, R¹¹, n and p 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

QUINAZOLINE COMPOUNDS USEFUL AS M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS FIELD OF THE INVENTION

The invention is directed to a class of quinazoline compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body. In particular, the invention is directed to a class of quinazoline compounds which are muscarinic M1 receptor positive allosteric modulators, and hence are useful in the treatment of Alzheimer’s Disease and/or other diseases mediated by the muscarinic M1 receptor. CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable. 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 E^peptide (AE^^^^ AE^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.

Thus, there remains a considerable need for identification of additional muscarinic M1 receptor positive allosteric modulators believed to be useful in the treatment of Alzheimer’s Disease and/or other diseases mediated by the muscarinic M1 receptor. SUMMARY OF THE INVENTION

The present invention is directed to novel quinazoline compounds of generic formula (I) described below, or pharmaceutically acceptable salts thereof, which are useful as M1 receptor positive allosteric modulators.

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 general Formula (I), 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), 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. DETAILED DESCRIPTION OF THE INVENTION

The present invention addresses the following compounds, compounds of (1)- (19): (1) A compound of Formula (I):

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 NR¹⁰ and the other occurrence(s) of X, when present, are CR^6AR^6B; each occurrence of Y is CR^6AR^6B; each occurrence of Z is independently CR⁷ or N; 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, or O,

(d) halogen,

(e)–CN,

(^f)–O-C ₁ ^-C ₆ ^alkyl,

(^g)–C ₁ ^-C ₆ ^alkyl,

(^h)–C ₂ ^-C ₆ ^alkenyl,

(i)–S(=O)_k–R²,

(j)–(C(O)O)_mN(R^3A)(R^3B),

(k)–OH, and

(l) -C(=O)-(O)_m–R⁴,

wherein said 6-membered aryl, said 5- or 6-membered heteroaryl, said–O-C₁-C₆ alkyl, said–C₁- ^C ₆ ^{alkyl and said–C} ₂ ^-C ₆ ^{alkenyl are 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; R², R⁴, and R⁵ are independently selected from the group consisting of: hydrogen, -C₁-C₆ alkyl, ^and–C ₂ ^-C ₆ ^{alkenyl, wherein said -C} ₁ ^-C ₆ ^{alkyl and said–C} ₂ ^-C ₆ ^{alkenyl are optionally substituted} with up to four halogen; R^3A and R^3B are independently selected from the group consisting of:

(a) hydrogen,

(b)–C_1-C₆ alkyl,

(c)–C_3-C₆ cycloalkyl,

(d)–C(=O)-R⁴,

(e)–C(=O)-O-R⁴, and

(f)–S(O)₂-R⁴,

or, alternatively, R^3A and R^3B, together with the attached nitrogen, form a 3-6 membered nitrogen-containing heterocyclic ring optionally having one to three additional heteroatoms selected from N, O and S; each occurrence of R^6Aand R^6B is independently selected from hydrogen, fluorine,–O-C₁-C₆ ^{alkyl, and -C} ₁ ^-C ₆ ^{alkyl, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said -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; each occurrence of R⁷ is independently hydrogen or halogen; ^{R8 and R9 are independently hydrogen, halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^alkyl,–C ₂ ^-C ₆ alkenyl,–C(=O)-(O)_m–R⁴,–N(R^3A)(R^3B), or–S(=O)_k–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said–C} ₁- ^C ₆ ^{alkyl, and said–C} ₂ ^-C ₆ ^{alkenyl are optionally substituted with one to three substituents} ^{independently selected from halogen and C} ₁ ^-C ₆ ^alkyl; or, alternatively, R⁸ and R⁹, together with their attached carbon atoms, form a 5-6 membered ring fused to the benzene to which R⁸ and R⁹ are attached wherein said 5-6 membered ring is selected from the group consisting of:

(a) a 5-6 membered cycloalkyl ring,

(b) a 5-6 membered heterocycloalkyl ring having one to three heteroatoms

selected from N, O and S, and

(c) a 5-membered heteroaryl ring having one to three heteroatoms selected from N, O and S;

and wherein said 5-6 membered cycloalkyl ring, said 5-6 membered heterocycloalkyl ring or said 5-membered heteroaryl ring is optionally substituted with 1-3 substituents independently ^{selected from halogen, oxo, 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–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said–C} ₁ ^-C ₆ ^{alkyl are optionally} substituted with one to three substituents independently selected from halogen and C₁-C₆ alkyl; ^{R10 is hydrogen, halogen, hydroxy,–O-C} ₁ ^-C ₆ ^{alkyl, -C} ₁ ^-C ₆ ^{alkyl,–S(=O)} _k ^-R2,–C₂-C₆ alkenyl,– ^{CN, -C(=O)-(O)} _m ^{-R4,–N(R3A)(R3B), -C} ₆ ^-C ₁₀ ^{aryl, -C} ₅ ^-C ₁₀ ^{heteroaryl, -C} ₅ ^-C ₁₀ ^{heterocycloalkyl,} ^{or -OC(=O)- R4, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said -C} ₁ ^-C ₆ ^{alkyl, said–C} ₂ ^-C ₆ ^{alkenyl, said -C} ₆- ^C ₁₀ ^{aryl, said -C} ₅ ^-C ₁₀ ^{heteroaryl and said -C} ₅ ^-C ₁₀ ^{heterocycloalkyl are optionally substituted with} ^{one to four substituents independently selected from halogen,–C} ₁ ^-C ₆ ^{alkyl, and–OC} ₁ ^-C ₆ ^alkyl; R¹¹ when present is selected from the group consisting of: (a) hydrogen,

(b) halogen, and

(c)–C_1-10 alkyl, optionally substituted with one to three substituents independently selected from oxo and–OH; k is 0, 1 or 2;

n is 0, 1 or 2;

m is 0 or 1;

p is 0 or 1; and the partially dashed double bond (“ ”) represents a single or double bond wherein:

(i) when p is 1, the dashed bond represents a single bond; and

(ii) when p is 0, the dashed bond represents a double bond; 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, p is 0, the dashed bond represents a double bond, each R⁷ is hydrogen, and each occurrence of X and Y is CH₂, R⁸ are R⁹ are not: i. hydrogen and–CH₃;

ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH_3;

(b) where R¹ is -Cl, one occurrence of Z is N and the other occurrence of Z is CH, p is 0, the dashed bond represents a double bond, each R⁷ is hydrogen, and each occurrence of X and Y is CH₂, R⁸ are R⁹ are not:

i. hydrogen and–CH₃;

ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH₃; and

(c) where R¹ is hydrogen, one occurrence of Z is N and the other occurrence of Z is CH, p is 0, the dashed bond represents a double bond, each R⁷ is hydrogen, and each occurrence of X and Y is CH₂, R⁸ are R⁹ are not:

i. hydrogen and–CH₃; ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH₃. (2) The compound of (1) or a pharmaceutically acceptable salt thereof wherein each occurrence of X is CR^6AR^6B. In a sub-embodiment hereof, each occurrence of X is CH₂. (3) The compound of (1) or a pharmaceutically acceptable salt thereof wherein one occurrence of X is C=O, O, S or NR¹⁰ and the other occurrence(s) of X, when present, are CR^6AR^6B. In a 1^st sub-embodiment hereof, one occurrence of X is C=O and the other occurrence(s) of X, when present, are CR^6AR^6B. In a 2^nd sub-embodiment hereof, one occurrence of X is C=O and the other occurrence(s) of X, when present, are CH₂. In a 3^rd sub-embodiment hereof, one occurrence of X is O and the other occurrence(s) of X, when present, are CR^6AR^6B. In a 4^th sub-embodiment hereof, one occurrence of X is O and the other occurrence(s) of X, when present, are CH₂. In a 5^th sub-embodiment hereof, one occurrence of X is S and the other occurrence(s) of X, when present, are CR^6AR^6B. In a 6^th sub-embodiment hereof, one occurrence of X is S and the other occurrence(s) of X, when present, are CH₂. In a 7^th sub-embodiment hereof, one occurrence of X is NR¹⁰ and the other occurrence(s) of X, when present, are

CR^6AR^6B. In a 8^th sub-embodiment hereof, one occurrence of X is NR¹⁰ and the other occurrence(s) of X, when present, are CH₂. (4) The compound of any of (1)-(3) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein each Y is CH₂. (5) The compound of any of (1)-(3) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein each Y is CH₂. (6) The compound of any of (1)-(5) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein each occurrence of Z is CR⁷. In a sub- embodiment thereof, each occurrence of Z is CH. (7) The compound of any of (1)-(5) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein at least one occurrence of Z is N. In a 1^st sub- embodiment hereof, one occurrence of Z is N and one occurrence of Z is CH. In a 2^nd sub- embodiment hereof, each occurrence of Z is N. (8) The compound of any of (1)-(7) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:

(a) hydrogen,

(b) a 6-membered aryl,

(d) halogen,

(e)–CN,

(^f)–O-C ₁ ^-C ₆ ^alkyl,

(^g)–C ₁ ^-C ₆ ^alkyl,

(^h)–C ₂ ^-C ₆ ^alkenyl,

(i)–S(=O)_k–R²,

(j)–(C(O)O)_mN(R^3A)(R^3B),

(k)–OH, and

(l) -C(=O)-(O)_m–R⁴,

wherein said 6-membered aryl, said 5- or 6-membered heteroaryl, said–O-C₁-C₆ alkyl, said–C₁- ^C ₆ ^{alkyl and said–C} ₂ ^-C ₆ ^{alkenyl are 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. In a 1^st sub-embodiment hereof, R¹ is hydrogen. In a 2^nd sub- embodiment hereof, R¹ is a 6-membered aryl optionally substituted with one to three

s^{ubstituents, 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. In a 3^rd sub-embodiment hereof, R¹ is a 5- 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. In a 4^th sub-embodiment hereof, 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. In a 5^th sub-embodiment hereof, 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. In a 6^th sub- embodiment hereof, R¹ is a 5-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-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. In a 7th sub-embodiment, R¹ is . In a 8^th sub-embodiment hereof, R¹ is a 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. In a 9^th sub- embodiment hereof, R¹ is halogen. In a 10^th sub-embodiment hereof, R¹ is -Cl. In a 11^th sub- embodiment hereof, R¹ is–CN. In a 12^th sub-embodiment hereof, 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. In a 13^th sub-embodiment hereof, R¹ is–OCH₃. In a 14^{th sub-embodiment hereof, R1 is–C} ₁ ^-C ₆ ^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. In a 15^th sub-embodiment hereof, R¹ is–CH₃. In a 16^{th sub-embodiment hereof, R1 is–C} ₂ ^-C ₆ ^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. In a 17^th sub-embodiment hereof, R¹ is–S(=O)_k–R². In a 18^th sub-embodiment hereof, R¹ is–SCH₃. In a 19^th sub-embodiment hereof, R¹ is–(C(O)O)_mN(R^3A)(R^3B). In a 20^th sub-embodiment hereof, R¹ is–OH. In a 21^st sub-embodiment hereof, R¹ is -C(=O)-(O)_m–R⁴. (9) The compound of any of (1)-(8) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R², R⁴, and R⁵ are independently selected from ^{the group consisting of: hydrogen, -C} ₁ ^-C ₆ ^{alkyl, and–C} ₂ ^-C ₆ ^{alkenyl, wherein said -C} ₁ ^-C ₆ ^alkyl and said–C₂-C₆ alkenyl are optionally substituted with up to four halogen. In a sub-embodiment hereof, R², R⁴, and R⁵ are independently selected from hydrogen and–CH₃. (10) The compound of any of (1)-(9) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R^3A and R^3B are independently selected from the group consisting of:

(a) hydrogen, (b)–C_1-C₆ alkyl,

(c)–C_3-C₆ cycloalkyl,

(d)–C(=O)-R⁴,

(e)–C(=O)-O-R⁴, and

(f)–S(O)₂-R⁴,

or, alternatively, R^3A and R^3B, together with the attached nitrogen, form a 3-6 membered nitrogen-containing heterocyclic ring optionally having one to three additional heteroatoms selected from N, O and S. In a sub-embodiment hereof, R^3A and R^3B are independently selected from the group consisting of hydrogen and–C_1-C₆ alkyl. (11) The compound of any of (1)-(10) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R^6Aand R^6B is

i^{ndependently 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 said -C} ₁ ^-C ₆ ^{alkyl, are optionally substituted with one to four substituents} independently selected from fluorine,–C₁-C₆ alkyl, and–OC₁-C₆ alkyl. In a 1^st sub-embodiment hereof, R^6Aand R^6B are independently selected from hydrogen and -C₁-C₆ alkyl, wherein said - C₁-C₆ alkyl is optionally substituted with up to four fluorine. In a 2^nd sub-embodiment hereof, R^6Aand R^6B are independently selected from hydrogen and–CH₃. (12) The compound of any of (1)-(11) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹ are independently hydrogen, ^{halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^alkyl,–C ₂ ^-C ₆ ^{alkenyl,–C(=O)-(O)} _m ^–R4,–

N(R^3A)(R^3B), or–S(=O)_k–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said–C} ₁ ^-C ₆ ^{alkyl, and said–C} ₂ ^-C ₆ alkenyl are optionally substituted with one to three substituents independently selected from ^{halogen and C} ₁ ^-C ₆ ^{alkyl. In a sub-embodiment, R8} and R⁹ are independently halogen, hydroxy, ^–O-C ₁ ^-C ₆ ^alkyl,–C ₂ ^-C ₆ ^{alkenyl,–C(=O)-(O)} _m ^–R4,–N(R^3A)(R^3B), or–S(=O)_k–R⁵, wherein said– ^O-C ₁ ^-C ₆ ^{alkyl, said–C} ₁ ^-C ₆ ^{alkyl, and said–C} ₂ ^-C ₆ ^{alkenyl are optionally substituted with one to} three substituents independently selected from halogen and C₁-C₆ alkyl. In a sub-embodiment ^{hereof, R8 and R9 are independently selected from hydrogen, halogen,–O-C} ₁ ^-C ₆ ^{alkyl, -C} ₁ ^-C ₆ ^{alkyl, and C} ₂ ^-C ₆ ^{alkenyl, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said–C} ₁ ^-C ₆ ^{alkyl, and said–C} ₂ ^-C ₆ alkenyl are optionally substituted with one to three halogen or C₁-C₆ alkyl. In a sub- embodiment, R⁸ are R⁹ are not (i) hydrogen and–CH₃; (ii)–CH₃ and hydrogen; (iii) hydrogen and hydrogen; or (iv)–CH₃ and–CH₃. (13) The compound of any of (1)-(11) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹, together with their attached carbon atoms, form a 5-6 membered ring fused to the benzene to which R⁸ and R⁹ are attached wherein said 5-6 membered ring is selected from the group consisting of:

(a) a 5-6 membered cycloalkyl ring,

(b) a 5-6 membered heterocycloalkyl ring having one to three heteroatoms

selected from N, O and S, and

N(R^3A)(R^3B), and–S(=O)_k–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said–C} ₁ ^-C ₆ ^{alkyl are optionally} substituted with one to three substituents independently selected from halogen and C₁-C₆ alkyl. (14) The compound of any of (1)-(13) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from the group consisting of: ^{hydrogen and -C} ₁ ^-C ₆ ^alkyl. (15) The compound of any of (1)-(14) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2. In a sub-embodiment hereof, n is 1.

(16) The compound of any of (1)-(15) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, the dashed bond represents a double bond, and R¹¹ is absent. (17) The compound of any of (1)-(15) or sub-embodiment thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1, the dashed bond represents a single bond, and R¹¹ is selected from the group consisting of:

(a) hydrogen, and

(b)–C_1-10 alkyl, optionally substituted with one to three substituents independently selected from oxo and–OH. (18) The compound which is:

(a) 8-chloro-6-((6-chloropyridin-3-yl)methyl)-3-(2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(b) 6-((6-chloropyridin-3-yl)methyl)-7,8-difluoro-3-(2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(c) 6-((6-chloropyridin-3-yl)methyl)-3-(3-hydroxytetrahydro-2H-pyran-4-yl)-8- methoxyquinazolin-4(3H)-one;

(d) 7-chloro-6-((6-chloropyridin-3-yl)methyl)-3-(2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(e) 7,8-dichloro-3-(2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one;

(f) 3-(2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)-7,8,9,10-tetrahydrobenzo[h]quinazolin-4(3H)-one;

(g) 3-(2-hydroxycyclohexyl)-1-methyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin- 3-yl)methyl)-1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one;

(h) 3-(2-hydroxycyclohexyl)-7,8-dimethyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(i) 3-(2-hydroxycyclohexyl)-7-methyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(j) 3-(2-hydroxycyclohexyl)-8-methyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(k) 7,8-dichloro-3-(2-hydroxycyclohexyl)-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(l) 3-(2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(m) 3-(2-hydroxycyclohexyl)-8-methyl-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(n) 7-chloro-3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(o) 7,8-dichloro-3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(p) 3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one; (q) 3-(3-hydroxytetrahydro-2H-pyran-4-yl)-6-((6-methylpyridin-3-yl)methyl)- 3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(r) 3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-7,8,9,10- tetrahydrobenzo[h]quinazolin-4(3H)-one;

(s) 3-(3-hydroxytetrahydro-2H-pyran-4-yl)-8-methoxy-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(t) 3-(2-hydroxycyclohexyl)-6-((6-methoxypyridin-3-yl)methyl)-8- methylquinazolin-4(3H)-one;

(u) 6-((6-chloropyridin-3-yl)methyl)-3-(2-hydroxycyclohexyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(v) 6-((6-chloropyridin-3-yl)methyl)-3-(3-hydroxytetrahydro-2H-pyran-4-yl)- 3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(w) 6-((6-chloropyridin-3-yl)methyl)-3-(2-hydroxycyclohexyl)-7,8,9,10- tetrahydrobenzo[h]quinazolin-4(3H)-one;

(x) 7,8-dichloro-6-((6-chloropyridin-3-yl)methyl)-3-(2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(y) 6-((6-chloropyridin-3-yl)methyl)-3-(2-hydroxycycloheptyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(z) 8-chloro-3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(aa) 3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-8- vinylquinazolin-4(3H)-one;

(bb) 8-ethyl-3-(2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(cc) 6-((6-chloropyridin-3-yl)methyl)-3-(2-hydroxycyclohexyl)-1-methyl- 1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one;

(dd) 3-(2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3-yl)methyl)-9,10- dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione;

(ee) 4-((6-chloropyridin-3-yl)methyl)-7-(2-hydroxycyclohexyl)-1-methyl-1,7- dihydro-6H-[1,2,3]triazolo[4,5-h]quinazolin-6-one;

(ff) 7-(2-hydroxycyclohexyl)-1-methyl-4-((6-methylpyridin-3-yl)methyl)-1,7- dihydro-6H-[1,2,3]triazolo[4,5-h]quinazolin-6-one; (gg) 4-((6-chloropyridin-3-yl)methyl)-7-(2-hydroxycyclohexyl)-1-methyl-1,7- dihydro-6H-imidazo[4,5-h]quinazolin-6-one;

or a pharmaceutically acceptable salt thereof. (19) The compound which is:

(a) 8-chloro-6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(b) 6-((6-chloropyridin-3-yl)methyl)-7,8-difluoro-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(c) 6-((6-chloropyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran- 4-yl)-8-methoxyquinazolin-4(3H)-one;

(d) 7-chloro-6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(e) 7,8-dichloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one;

(f) 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)-7,8,9,10-tetrahydrobenzo[h]quinazolin-4(3H)-one;

(g) 3-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-6-((6-(1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)-1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one;

(h) 3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(i) 3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(j) 3-((1S,2S)-2-hydroxycyclohexyl)-8-methyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(k) 7,8-dichloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one;

(l) 3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(m) 3-((1S,2S)-2-hydroxycyclohexyl)-8-methyl-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(n) 7-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one; (o) 7,8-dichloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(p) 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(q) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((6-methylpyridin-3- yl)methyl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(r) 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-7,8,9,10- tetrahydrobenzo[h]quinazolin-4(3H)-one;

(s) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-8-methoxy-6-((6- methylpyridin-3-yl)methyl)quinazolin-4(3H)-one;

(t) 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methoxypyridin-3-yl)methyl)-8- methylquinazolin-4(3H)-one;

(u) 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(v) 6-((6-chloropyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran- 4-yl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(w) 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8,9,10- tetrahydrobenzo[h]quinazolin-4(3H)-one;

(x) 7,8-dichloro-6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one;

(y) 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycycloheptyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one;

(z) 8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(aa) 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-8- vinylquinazolin-4(3H)-one;

(bb) 8-ethyl-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one;

(cc) 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-1-methyl- 1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one;

(dd) 3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3- yl)methyl)-9,10-dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione; (ee) 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl- 1H-[1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one;

(ff) 7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-4-((6-methylpyridin-3-yl)methyl)- 1,7-dihydro-6H-[1,2,3]triazolo[4,5-h]quinazolin-6-one;

(gg) 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)-1- methyl-1,7-dihydro-6H-imidazo[4,5-h]quinazolin-6-one; or a pharmaceutically acceptable salt thereof. 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. Reference to compounds of the invention specifically includes different embodiments of Formula (I), embodiments (1)-(19) and sub-embodiments thereof, and individual compounds described herein. Other specific embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt of any of embodiments (1)-(19), 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 a compound or pharmaceutically acceptable salt of any of embodiments (1)-(19), 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) (or pharmaceutically acceptable salt) 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 or pharmaceutically acceptable salt of any of embodiments (1)-(19).

(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 or pharmaceutically acceptable salt of any of embodiments (1)-(19).

(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

The present invention also includes a compound or pharmaceutically acceptable salt of any of embodiments (1)-(19), (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 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 is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula (I) 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) or its salt per se; i.e., the purity of the active ingredient in the composition. Methods of Use of the Compounds of the Invention:

The present invention is directed to the use of the compounds 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 (eg, 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. 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 are 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 and 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 characterized 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), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. Combinations of substituents and/or variables 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 mg, 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 including 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 including 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- C₄)alkylene-aryl, 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 and considered herein to be compounds of the invention. 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). 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 the present invention 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; ACN– acetonitrile; BINAP = 2,2'-bis(diphenylphosphino)-1,1'- binaphthyl; BIPPYPHOS = 5-(Di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; B-NADP+ = E - Nicotinamide adenine dinucleotide phosphate; BOC = tert-butyloxycarbonyl; BOP = Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; t- BuOH = tert-butyl alcohol; CELITE = diatomaceous earth; CHO = Chinese hamster ovary; DCE = 1,2-dichloroethane; DIPEA = N,N-Diisopropylethylamine; DME = Dimethoxyethane; DMEM = Dulbecco’s Modified Eagle Medium (High Glucose); DMF = N,N-dimethylformamide;

DMFDMA (or DMF/DMA) = N,N-dimethylformamide dimethylacetal; DMSO =

dimethylsulfoxide; DPPA = diphenyl phosphoryl azide; FBS = fetal bovine serum; FDH = formate dehydrogenase; FLIPR = Fluorometric Imaging Plate Reader System; GDH = glucose dehydrogenase; h = hours; HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HPLC = high performance liquid chromatography; LDH = lactate dehydrogenase; LRMS= low resolution mass spectometry; m-CPBA = meta- chloroperoxybenzoic acid; Me = methyl; MeOH = methanol; MOMCl = Methyl chloromethyl ether; MtBE = methyl tert-butyl ether; MW = microwave; NAD = Nicotinamide adenine dinucleotide; NBS = N-bromosuccinimide; NEAA = non-essential amino acids; NMP = N- Methyl-2-pyrrolidinone; NMR = nuclear magnetic resonance; OTBS = (tert- butyldimethylsilyl)oxy); Pd/C= palladium on carbon; Pd₂(dba)₃ = tris(dibenzylideneacetone) dipalladium; PMB-Amine = 4-Methoxybenzylamine; RT = room temperature; TBAF = Tetra-n- butylammonium fluoride; TBAI = tetrabutylammonium iodide; TBSOTf = tert- butyldimethylsilyl trifluoromethanesulfonate; TEA = trimethylamine; Tetramethyl di-tBuXPhos = 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; THF= tetrahydrofuran; TMEDA = tetramethylethylenediamine; and TMF = 2,2,6,6- tetramethylpiperidine. Several methods for preparing the compounds of this invention are illustrated in the schemes and examples herein so that the invention might be more fully understood. The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.

Starting materials useful for the preparation of the compounds in the present invention are known in the art, or may be prepared using chemical methodologies known to those skilled in the art or as illustrated herein.

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). Intermediate (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol

Preparation of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol:

A jacketed flask equipped with an overhead stirrer and a thermocouple was charged with 23.0 L of MeOH, and cooled to 5 °C. Potassium hydroxide (1.574 kg, 28.05 mol) was added to the flask, and the resulting solution was aged until homogeneous and then re- cooled to 5 °C. Tetrahydro-4H-pyran-4-one (1.00 kg, 10.0 mol) was then added at a steady rate over 20 min, and the resulting solution was aged for 20-30 minutes. A solution of iodine (2.778 kg, 10.95 mol) in 18.5 L of MeOH was then added via a mechanical pump at a steady rate over 90-100 minutes. After an additional 30 minutes, the solution was warmed to room temperature and toluene (42.0 L) was added. The resulting slurry was concentrated in vacuo to a volume of ~8.4 L. Additional toluene (8.4 L) was added and the resulting solution was concentrated to a volume of 8.4 L 2x. The resulting slurry was then filtered, and the filter cake was rinsed 2x with toluene (4.0 L). The combined toluene streams were concentrated to ~6 L, and the product was extracted 2x with water (3.0 L) to provide 4,4-dimethyoxytetrahydro-2H-pyran-3-ol.

To a solution of the above compound (1.00 kg, 6.17 mol) in 5 L of water was added acetic acid to a pH of 5.2-5.4. The mixture was diluted with acetonitrile (4.0 L), and ruthenium trichloride hydrate (6.4 g, 0.028 mol) was added and rinsed in with additional acetonitrile (1.0 L). The flask was placed in a room temperature water bath and a solution of sodium bromate (650 g, 4.31 mol) in water (1.95 L) was added slowly over ~30 min, keeping the temperature below 30 °C. After 2 hours, potassium bicarbonate (430 g, 4.30 mol), sodium thiosulfate (1.07 kg, 4.31 mol), potassium chloride (500 g, 6.71 mol) and acetonitrile (5 L) were added sequentially. The layers were separated and the aqueous layer was extracted 3x with acetonitrile (10 L). The combined organic extracts were concentrated to ~4 L. Toluene (5 L) was then added and the mixture was re-concentrated to 4 L 4x. The mixture was then diluted with toluene (7 L) and filtered to remove solids. The filter cake was washed 3x with toluene (2 L) and the combined filtrate and washes were concentrated to a total volume of 3 L to provide an organic solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one.

To a 3L 3-neck RB flask with overhead stirring, thermocouple and heating mantle was added sodium dihydrogenphosphate (96.0 g, 800 mmol) in 1.6 L of water. Sodium hydroxide (29 mL, 50 wt%) was added to a pH 7.13, followed by hydrochloric acid (5 mL, 6 N) to a pH 7.02.

The above organic solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one was extracted 3x with phosphate buffered water (0.55 L). D-glucose (180 g, 100 mmol) was added to the combined aqueous extracts, and the solution was heated to 30 °C. When the solution exceeded 27 °C upon heating, E-NADP+ (1.60 g, 499 mmol), GDH-103 (1.60 g, 499 mmol; commercially available from Codexis (Redwood City, Calif., USA)), and KRED-130 (1.60 g, 499 mmol; commercially available from Codexis (Redwood City, Calif., USA)) were added and the mixture was stirred for 17 h at 30 °C. KRED-130 can be obtained from available Codex KRED screening kits including the Codex Transaminase panel enzyme P1G5 products.

Potassium chloride (200g, 2.68 mol) and acetonitrile (1.3 L) were added. After 30 min, the reaction mixture was transferred to a 6 L separatory funnel and additional MeCN (0.67 L) and toluene (0.87 L) were added. The aqueous layer was back extracted 1x with a mixture of acetonitrile (1.95L) and toluene (0.65 L), and 1x with acetonitrile (1.5 L). The combined organic extracts were concentrated in vacuo to provide (3S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol. A solution of the above compound (72.0 g, 0.444 mol) in 750 mL of THF was added to a 2L RB flask with overhead stirring, thermocouple, heating mantle and N₂ inlet. After 15 h, sodium tert-butoxide (48.3 g, 492 mmol) was added in one portion, and the mixture was heated to 35 °C for 1 h, and aged at 22 °C for 1hr. Tetrabutylammonium iodide (8.19 g, 22.2 mmol) and benzyl bromide (56.5 ml, 466 mmol) were added, and the mixture was heated to 50°C for 2 h. The solution was cooled to 25 °C, and water (750 mL) and MtBE (2.25 L) were added. The organic layer was separated from the aqueous and concentrated in vacuo. The resultant oil was purified via silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes to provide (3S)-3-(benzylyoxy)-4,4-dimethoxytetrahydro-2H-pyran.

2 N HCl (300 mL, 0.600 mol) was added to a solution of the above compound (61.1 g, 225 mmol ) in 300 mL of THF. After 1.5 hours, saturated aqueous potassium carbonate (60 mL) was added via addition funnel to a pH 7.4. The aqueous layer was extracted 3x with MtBE (300 mL) and the combined organic extracts were concentrated in vacuo to provide crude (3S)-3-(benzyloxy)tetrahydro-4H-pyran-4-one.

NAD (2.2 g, 3.21 mmol), pyridoxal-5-phosphate (2.2 g, 8.90 mmol), LDH (0.45 g, 0.22 mol), FDH (4.5 g, 0.20 mol), and TA P1G5 (4.5 g, 0.22 mol) were added to a solution of L-Alanine (200 g, 2.24 mol), sodium formate (76.0 g, 1.12 mmol), and sodium phosphate dibasic (28.7 g, 202 mmol) in 2.25 L of water adjusted to pH 7.5. After all the components were completely dissolved, (3S)-3-(benzyloxy)tetrahydro-4H-pyran-4-one (45 g, 0.22 mol) was added and the pH was adjusted to pH 7.25 with 6 N HCl and then aged at 30 °C. After 15 hours, potassium carbonate (700 g, 5.06 mol) was added slowly, followed by ethyl acetate (2.2 L). The mixture was filtered through a bed of SOLKA FLOC powdered cellulose and the cake was washed with ethyl acetate (250 mL). The combined filtrates were separated and the aqueous layer was extracted a second time with ethyl acetate (2 L). The combined organic extracts were concentrated in vacuo to provide crude (3R, 4S)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine.

Concentrated hydrochloric acid (23.3 mL) was added to a solution of the above compound (38.8 g, 0.187 mol) in 730 mL of methanol. The solution was subjected to

hydrogenation at 40 psi H₂, at 25 °C over 10% Pd/C (5.8 g). After 15 hours, the mixture was filtered through SOLKA FLOC powdered cellulose and the filter cake was washed 5x with methanol (100 mL). The combined filtrate and washes were concentrated in vacuo to provide (3R, 4S)-4-aminotetrahydro-2H-pyran-3-ol.

The title intermediate is employed in procedures where a (R)-tetrahydro-2H- pyran-3-ol group is sought in place of a cyclohexanol group as, for example in Compounds 7, 26, 28 and 31. The title intermediate therefore may be substituted in the procedures for (1S, 2S)-2- aminocyclohexanol. Example 1, Compounds 1-4

- - - - - - , - - ohexyl)-7,8-dimethylquinazolin- 4(3H)-one, Compound 1

Step 1: Preparation of methyl 2-hydroxy-3,4-dimethylbenzoate

Thionyl chloride (8.78 mL, 120 mmol) was added slowly to a solution of 2- hydroxy-3,4-dimethylbenzoic acid (2.00 g, 12.0 mmol) in methanol (30 mL) at 0 °C. The mixture was heated at 65 °C for 16 hours. The mixture was concentrated in vacuo and the resulting residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound.

Step 2: Preparation of methyl 3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

Trifluoromethanesulfonic anhydride (2.34 mL, 13.9 mmol) was added slowly to a stirred solution of methyl 2-hydroxy-3,4-dimethylbenzoate (500 mg, 2.77 mmol) in pyridine (10 mL) at 0 °C. The mixture was warmed to room temperature and heated at 50 °C for 2 hours. The mixture was cooled to ambient temperature, treated with ice cold water (50 mL), and then extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound.

Step 3: Preparation of methyl 2-((4-methoxybenzyl)amino)-3,4-dimethylbenzoate

A mixture of methyl 3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (530 mg, 1.697 mmol) and cesium carbonate (1.66 g, 5.09 mmol) in toluene (15 mL) was sparged under nitrogen and then treated with palladium(II) acetate (38.1 mg, 0.170 mmol), BINAP (211 mg, 0.339 mmol) and 4-methoxybenzylamine (0.443 mL, 3.39 mmol). The mixture was again sparged under nitrogen for 3 minutes and then heated at 80 °C for 16 hours. The mixture was cooled to ambient temperature and then filtered through a bed of silica gel and CELITE, and then washed with ethyl acetate (50 mL). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 300.2 for [M + H]⁺.

Step 4: Preparation of methyl 2-amino-3,4-dimethylbenzoate

Palladium on carbon (100 mg, 0.940 mmol) was added to the solution of methyl 2-((4-methoxybenzyl)amino)-3,4-dimethylbenzoate (400 mg, 1.34 mmol) in ethyl acetate (15 mL). The mixture was sparged under hydrogen (1 atm) and stirred at room temperature for 3 hours. The mixture was sparged under nitrogen and then filtered through a bed of CELITE, which was washed with ethyl acetate (50 mL). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 179.8 for [M + H]⁺.

Step 5: Preparation of methyl 2-amino-5-bromo-3,4-dimethylbenzoate

Bromine (0.062 mL, 1.205 mmol) in 1:1 mixture of carbon tetrachloride (3 mL) and 1,4-dioxane (3 mL) was added to a solution of methyl 2-amino-3,4-dimethylbenzoate (180 mg, 1.00 mmol) in 1:1 mixture of carbon tetrachloride (3 mL) and 1,4 -dioxane (3 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and then treated with saturated aqueous sodium bicarbonate (10 mL) slowly. The mixture was extracted with ethyl acetate (3 x 25 mL) and the combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 257.8 for [M + H]⁺.

Step 6: Preparation of 2-amino-5-bromo-3,4-dimethylbenzoic acid

Lithium hydroxide (111 mg, 4.65 mmol) was added to a stirred solution of methyl 2-amino-5-bromo-3,4-dimethylbenzoate (200 mg, 0.775 mmol) in a 1:1:1 mixture of MeOH (4 mL), water (4 mL) and THF (4 mL). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo, treated with water (30 mL), and acidified with 6N HCl to pH ~ 3. The resultant solid was filtered and dried in vacuo to provide the title compound; mass ion [ES+] of 246.2 (⁸¹Br) for [M + H]⁺.

Step 7: Preparation of 2-amino-5-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-3,4- dimethylbenzamide

BOP (333 mg, 0.754 mmol) was added to a stirred solution of 2-amino-5-bromo- 3,4-dimethylbenzoic acid (160 mg, 0.656 mmol) and triethylamine (0.228 mL, 1.639 mmol) in a mixture of dichloromethane (7 mL) and DMF (2 mL) at 0 °C, followed by the addition of (1S,2S)-2-aminocyclohexanol (87 mg, 0.75 mmol). The mixture was warmed to room

temperature, stirred for 3 hours, and then treated with aqueous saturated sodium bicarbonate (5 mL). The mixture was extracted with dichloromethane (3 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 341.2 for [M + H]⁺. Step 8: Preparation of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethylquinazolin- 4(3H)-one

A solution of 2-amino-5-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dimethyl benzamide (150 mg, 0.440 mmol) in N,N-dimethylformamide dimethylacetal (4.00 mL, 29.9 mmol) was heated at 120 °C for 5 hours, cooled to ambient temperature, and then concentrated in vacuo. The residue was treated with water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine (10 mL), dried sodium sulfate, filtered, and concentrated in vacuo. The solid obtained was triturated with hexane (10 mL), filtered, and dried in vacuo to provide the title compound that gave a mass ion [ES+] 353.0 (⁸¹Br) for [M + H]⁺.

Step 9: Preparation of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)- 7,8-dimethylquinazolin-4(3H)-one

((6-chloropyridin-3-yl)methyl)zinc(II) chloride (0.5 M in THF, 2.28 mL, 1.14 mmol) was added to a solution of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-7,8- dimethylquinazolin-4(3H)-one (160 mg, 0.456 mmol) in THF (8 mL) at 0 °C, followed by the addition of bis(tri-tert-butylphosphine)palladium(0) (11.6 mg, 0.023 mmol). The mixture was warmed to room temperature and stirred for 15 minutes. The mixture was treated with aqueous saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (60 % ethyl acetate in petroleum ether) to provide the title compound. ¹H NMR (400MHz, CDCl₃): δ 8.24 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.55– 7.31 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.74– 4.57 (m, 1H), 4.12 (s, 2H), 3.98– 3.90 (m, 1H), 2.57 (s, 3H), 2.26– 2.21 (m, 4H), 2.09– 1.99 (m, 1H), 1.90– 1.82 (m, 3H), 1.66– 1.41 (m, 3H) ppm. LRMS C₂₂H₂₅ClN₃O₂: calc’d 398.2, obs 398.2 (M+H) ⁺. Utilizing the procedures described above, substituting the appropriate hydroxy ester for methyl 2-hydroxy-3,4-dimethylbenzoate, the following compounds were obtained:

₂

₂

Example 2, Compounds 5-8 6-((6-chloropyridin-3-yl)methyl)-7,8-difluoro-3-((1S,2S)-2-hydroxycyclohexyl)quinazolin- 4(3H)-one, Compound 5

Step 1: Preparation of 6-bromo-2,3-difluorobenzoic acid

2,2,6,6-tetramethylpiperidine (15.9 g, 113 mmol) and 4-bromo-1,2- difluorobenzene (15.0 g, 78 mmol) were added slowly to a stirred solution of n-butyl lithium (2.5 M in hexane, 37.3 mL, 93 mmol) in THF (120 mL) at -78 °C. The mixture was stirred at -78 °C for 2 hours and then poured onto crushed dry ice. After evaporation of CO₂ from the mixture, water was added and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The combined organic extracts were then washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (70– 90 % ethyl acetate in petroleum ether). Trituration with dichloromethane afforded the title compound.

Step 2: Preparation of tert-butyl (6-bromo-2,3-difluorophenyl)carbamate

Triethylamine (5.18 mL, 37.1 mmol) and diphenyl phosphoryl azide (5.57 g, 20.2 mmol) were added to a stirred solution of 6-bromo-2,3-difluorobenzoic acid (4.00 g, 16.9 mmol) in THF (35 mL) at room temperature under nitrogen. The mixture was stirred at room temperature for 3 hours and then heated at 80 °C for 2 hours. The mixture was cooled to room temperature and t-butanol was added to the mixture slowly. The mixture was heated to 80 °C for 16 hours. The mixture was treated with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (2– 4 % ethyl acetate in petroleum ether) to provide the title compound.

Step 3: Preparation of methyl 2-((tert-butoxycarbonyl)amino)-3,4-difluorobenzoate

Sodium acetate (0.799 g, 9.74 mmol) was added to a stirred solution of tert-butyl (6-bromo-2,3-difluorophenyl)carbamate (1.00 g, 3.25 mmol) in methanol (15 mL). The mixture was sparged under nitrogen for 10 minutes and then treated with [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.475 g, 0.649 mmol). The mixture was sparged under nitrogen for 5 minutes and then was heated to 75 °C for 16 hours under 5 Kg pressure of carbon monoxide. The mixture was cooled to ambient temperature, filtered through a bed of CELITE, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2– 4 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 188.0 for [M - Boc]⁺.

Step 4: Preparation of methyl 2-amino-3,4-difluorobenzoate Trifluoroacetic acid (0.500 mL, 6.49 mmol) was added to a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)-3,4-difluorobenzoate (450 mg, 1.57 mmol) in

dichloromethane (5 mL) under nitrogen at 0 °C. After stirring at 0 °C for 5 minutes, the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and the residue was washed with aqueous saturated sodium bicarbonate, which was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2– 4 % ethyl acetate in petroleum ether) to provide the title compound.

Step 5: Preparation of methyl 2-amino-5-bromo-3,4-difluorobenzoate

N-bromosuccinimide (366 mg, 2.06 mmol) was added portion-wise to a stirred solution of methyl 2-amino-3,4-difluorobenzoate (350 mg, 1.87 mmol) in DMF (8 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 5 minutes, warmed to room temperature and further stirred for 1 hour. Ice-cold water was added to the mixture and was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column

chromatography (2– 4 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 267.9 for [M + H]⁺.

Step 6: Preparation of 2-amino-5-bromo-3,4-difluorobenzoic acid

Lithium hydroxide monohydrate (117 mg, 2.80 mmol) was added to a stirred solution of methyl 2-amino-5-bromo-3,4-difluorobenzoate (250 mg, 0.933 mmol) in a mixture of THF (5 mL), water (2 mL) and MeOH (2 mL) at 0 °C. After stirring at 0 ^ºC for 5 minutes, the mixture was stirred at room temperature for an additional 16 hours. The mixture was concentrated in vacuo and acidified with hydrochloric acid to a pH ~3. The residue was extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to provide the title compound mass ion [ES+] of 253.9 for [M + H]⁺. Step 7: Preparation of 2-amino-5-bromo-3,4-difluoro-N-((1S,2S)-2-hydroxycyclohexyl) benzamide

BOP (360 mg, 0.815 mmol), (1S,2S)-2-aminocyclohexanol (94 mg, 0.81 mmol) and triethylamine (0.259 ml, 1.86 mmol), respectively, were added to a stirred solution of 2- amino-5-bromo-3,4-difluorobenzoic acid (180 mg, 0.709 mmol) in a mixture of dichloromethane (5 mL) and DMF (1.5 mL) at room temperature. 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 sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (25 - 30 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of (⁸¹Br) 351.0

Step 8: Preparation of 6-bromo-7,8-difluoro-3-((1S,2S)-2-hydroxycyclohexyl) quinazolin- 4(3H)-one

A solution of 2-amino-5-bromo-3,4-difluoro-N-((1S,2S)-2- hydroxycyclohexyl)benzamide (160 mg, 0.456 mmol) in N,N-Dimethylformamide dimethyl acetal (301 μL, 2.269 mmol) was heated at 110 °C for 12 hours. The reaction mixture was cooled to room temperature, ice water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the crude product. The crude thus obtained was purified over silica gel using a gradient elution of 40 - 60 % ethyl acetate in petroleum ether to yield the title compound that gave a mass ion [ES+] of (⁸¹Br) 361.2 for [M + H]⁺.

Step 9: Preparation of 6-((6-chloropyridin-3-yl)methyl)-7,8-difluoro-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one

Bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) was added to a stirred solution of 6-bromo-7,8-difluoro-3-((1S,2S)-2-hydroxycyclohexyl)quinazolin-4(3H)-one (70 mg, 0.19 mmol) in THF (5 mL) at 0 °C. The mixture was stirred for 10 minutes and then treated with (2-chloro-5-pyridyl)methylzinc chloride solution (0.5 M in THF, 110 mg, 0.487 mmol) dropwise. The mixture was stirred for 3 hours at room temperature, treated with aqueous saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2 x 25 mL). The organic extracts were washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (40 % ethyl acetate in petroleum ether) to provide the title compound. ¹H NMR (400MHz , DMSO-d₆): δ 8.50 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.21 (s, 2H), 3.98– 3.85 (m, 1H), 2.05– 1.95 (m, 1H), 1.83– 1.69 (m, 4H), 1.34– 1.30 (m, 3H) ppm. LRMS C₂₀H₁₉ClF₂N₃O₂: calc’d 406.1, obs 406.2 (M+H) ⁺. Utilizing the procedures described above, substituting the appropriate aminoester for methyl 2- amino-3,4-difluorobenzoate, the following compounds were obtained:

₂

₄

(m, 1H), 1.82– 1.79

(m, 1H) ppm

Example 3, Compounds 9-15 3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)quinazolin-4(3H)-one, Compound 9

Scheme

A stirred solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2- hydroxycyclohexyl)-7,8-dimethylquinazolin-4(3H)-one (Compound 1, 60 mg, 0.15 mmol), sodium carbonate (48 mg, 0.45 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (78 mg, 0.38 mmol) in a mixture of 1,4-dioxane (6 mL) and water (2 mL) was sparged under nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (8.7 mg, 7.5 μmol) was added, the vessel was sealed, and then the mixture was heated at 100 °C for 16 hours. The mixture was cooled to room temperature and treated with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried with sodium sulfate, filtered, 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. ¹H NMR

(400MHz, CD₃OD): δ 8.44 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.21– 8.17 (m, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 4.39 (s, 2H), 4.20– 4.10 (m, 1H), 4.03 (s, 3H), 2.63 (s, 3H), 2.40 (s, 3H), 2.20– 2.10 (m, 1H), 1.99– 1.80 (m, 4H), 1.50– 1.48 (m, 3H) ppm.

LRMS C₂₆H₃₀N₅O₂: calc’d 444.2, obs 444.2 (M+H) ⁺. Utilizing the procedures described above, substituting the appropriate chloropyridine for 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8- dimethylquinazolin-4(3H)-one, the following compounds were obtained:

₂

, . – . m,

3H) ppm (CDCl3): δ.8.40 (s, 1H),

Example 4, Compounds 16-19 3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethyl-6-((6-(methylthio)pyridin-3- yl)methyl)quinazolin-4(3H)-one, Compound 16

Scheme

Sodium thiomethoxide (66 mg, 0.94 mmol) was added to a microwave vial containing a solution of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8- dimethylquinazolin-4(3H)-one (Compound 1, 75 mg, 0.19 mmol) in N-Methyl-2-pyrrolidinone (3.0 ml) at room temperature. The vial was sealed and heated at 90 °C in a microwave for 30 minutes. The mixture was cooled to room temperature, treated with water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, 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.¹H NMR (400MHz, CD₃OD): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.81– 7.78 (m, 1H), 7.55 (d, J = 8.5 Hz, 1H), 4.49– 4.42 (m, 1H), 4.26 (s, 2H), 4.20– 4.10 (m, 1H), 2.68 (s, 3H), 2.60 (s, 3H), 2.37 (s, 3H), 2.20– 2.15 (m, 1H), 1.98– 1.80 (m, 4H), 1.50– 1.48 (m, 3H) ppm. LRMS C₂₃H₂₈N₃O₂S: calc’d 410.2, obs 410.2

(M+H) ⁺. Utilizing the procedures described above, substituting the appropriate chloropyridine for 6-((6- chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethylquinazolin-4(3H)-one, the following compounds were obtained: +

Example 5, Compounds 20-28 3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethyl-6-((6-methylpyridin-3-yl)methyl)quinazolin- 4(3H)-one, Compound 20

Scheme

Tetramethyltin (45 mg, 0.25 mmol) was added to a stirred solution of 6-((6- chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethylquinazolin-4(3H)-one (Compound 1, 50 mg, 0.13 mmol) in DMF (2 mL) at room temperature under nitrogen, followed by addition of bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol). The mixture was heated at 100 °C for 6 hours, cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, 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 yield the title compound. ¹H NMR (400MHz, CD₃OD): δ 8.28– 8.23 (m, 2H), 7.91 (s, 1H), 7.50 (dd, J = 8.0, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H), 4.18– 4.05 (m, 1H), 2.59 (s, 3H), 2.51 (s, 3H), 2.32 (s, 3H), 2.22– 2.16 (m, 1H), 1.96– 1.84 (m, 3H), 1.49– 1.40 (m, 4H) ppm. LRMS C₂₃H₂₈N₃O₂: calc’d 378.2, obs 378.4 (M+H) ⁺. Utilizing the procedures described above, substituting the appropriate chloropyridine for 6-((6- chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7,8-dimethylquinazolin-4(3H)-one, the following compounds were obtained: ,

O₂ .2 2

O₂ .2 4

(DMSO-d6): δ 8.40 (s,

=

3 .2

2 .2

4 .2

1H) ppm Example 6, Compound 29 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methoxypyridin-3-yl)methyl)-8-methylquinazolin- 4(3H)-one, Compound 29

In a microwave vial containing a solution of 6-((6-chloropyridin-3-yl)methyl)-3- ((1S,2S)-2-hydroxycyclohexyl)-8-methylquinazolin-4(3H)-one (Compound 3, 100 mg, 0.261 mmol) in N-Methyl-2-pyrrolidinone (4.0 mL) at room temperature was added sodium methoxide (42.2 mg, 0.782 mmol). The vial was sealed and heated to 140 °C in a microwave reactor for 1 hour. The mixture was cooled to room temperature, treated with water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, 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 yield the title compound.¹H NMR (400MHz , CD₃OD): δ 8.26 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.56– 7.53 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 4.50 (br s, 1H), 4.12– 4.06 (m, 1H), 4.04 (s, 2H), 3.89 (s, 3H), 3.70– 3.60 (m, 1H), 2.57 (s, 3H), 2.17– 2.16 (m, 1H), 1.97– 1.84 (m, 4H), 1.50– 1.45 (m, 3H) ppm. LRMS C₂₂H₂₆N₃O₃: calc’d 380.2, obs 380.2 (M+H) ⁺. Example 7, Compounds 30-34 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-3,7,8,9-tetrahydro-4H- cyclopenta[h]quinazolin-4-one, Compound 30

Step 1: Preparation of 2,3-dihydro-1H-inden-4-ol

Sodium cyanoborohydride (22.3 g, 354 mmol) was added to a stirred solution of 4-hydroxy-2,3-dihydro-1H-inden-1-one (17.5 g, 118 mmol) and zinc(II) iodide (113 g, 354 mmol) in dry 1,2-dichloroethane (400 mL) at 0 °C. The mixture was refluxed at 80 °C for 2 hours, cooled to room temperature, treated with water, and then extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (8 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 135.0 for [M + H]⁺

Step 2: Preparation of 4-(methoxymethoxy)-2,3-dihydro-1H-indene

NaH (6.53 g, 163 mmol) was added to a stirred solution of 2,3-dihydro-1H-inden- 4-ol (7.3 g, 54 mmol) in THF (100 mL) at 0 °C under nitrogen. The mixture was warmed to ambient temperature, stirred for 1 hour, re-cooled to 0 °C, and then treated with MOMCl (6.20 mL, 82 mmol). The mixture was warmed to ambient temperature and stirred at room

temperature for an additional 1 hour. The mixture was cooled, diluted with cold water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound.¹H NMR (400MHz ,CDCl₃): δ 7.13– 7.08 (m, 1H), 6.93– 6.86 (m, 2H), 5.20 (s, 2H), 3.41 (s, 3H), 2.96– 2.88 (m, 4H), 2.13– 2.03 (m, 2H) ppm.

Step 3: Preparation of 4-(methoxymethoxy)-2,3-dihydro-1H-indene-5-carbaldehyde

TMEDA (8.47 mL, 56.1 mmol) was added to a solution of the 4- (methoxymethoxy)-2,3-dihydro-1H-indene (5.00 g, 28.1 mmol), under nitrogen, in diethyl ether (50 mL). The mixture was cooled to ^20 °C, treated with BuLi (22.44 mL, 2.5 M in hexane, 56.1 mmol), and the resultant solution was stirred for 30 minutes. The mixture was cooled to ^78 °C, treated with DMF (4.34 mL, 56.1 mmol), and then slowly warmed to ^40 °C over 1 hour. The mixture was treated with aqueous saturated NH₄Cl and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column

chromatography (0– 1 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 207.4 for [M + H]⁺.

Step 4: Preparation of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehyde

Aqueous HCl (1.5 N, 50 mL, 75 mmol) was added to a stirred solution of 4- (methoxymethoxy)-2,3-dihydro-1H-indene-5-carbaldehyde (4.00 g, 19.4 mmol) in THF (100 mL) at room temperature. The mixture was heated at 65 °C for 4 hours, cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water, and brine. The extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 10 % ethyl acetate in petroleum ether) to provide the title compound.¹H NMR (400MHz ,CDCl₃): δ 11.14 (s, 1H), 9.84 (s, 1H), 7.36 (d, J = 10.3 Hz, 1H), 6.91 (d, J = 10.3 Hz, 1H), 2.99– 2.90 (m, 4H), 2.19– 2.09 (m, 2H) ppm.

Step 5: Preparation of methyl 4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate

NaCN (0.755 g, 15.4 mmol) was added to a stirred solution of 4-hydroxy-2,3- dihydro-1H-indene-5-carbaldehyde (2.50 g, 15.4 mmol) in a mixture of MeOH (120 mL) and dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour, cooled to 0 °C, and then treated with manganese dioxide (1.34 g, 15.4 mmol). The mixture was warmed to room temperature, stirred for an additional 16 hours, and then treated with aqueous saturated sodium hydrogen sulfite at 0 °C. The mixture was warmed to ambient temperature, stirred for 1 hour, and then diluted with water. The mixture was extracted with dichloromethane and the combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column

chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound.¹H NMR (400MHz ,CDCl₃): δ 10.86 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.94 (s, 3H), 2.97– 2.92 (m, 4H), 2.17– 2.09 (m, 2H) ppm.

Step 6: Preparation of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-indene-5- carboxylate

Triflic anhydride (2.64 mL, 15.6 mmol) was added to a stirred solution of methyl 4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (1.00 g, 5.20 mmol) in pyridine (20 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred for 3 hours. The mixture was cooled to 0 qC, diluted with ice-cold water (25 mL) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 1 % ethyl acetate in petroleum ether) to provide the title compound.

Step 7: Preparation of methyl 4-((4-methoxybenzyl)amino)-2,3-dihydro-1H-indene-5- carboxylate

A mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-indene-5- carboxylate (1.00 g, 3.08 mmol) and cesium carbonate (3.01 g, 9.25 mmol) in toluene (40 mL) was sparged under nitrogen and then treated with palladium(II) acetate (0.138 g, 0.617 mmol), R(+)BINAP (0.768 g, 1.23 mmol) and 4-methoxybenzylamine (0.846 g, 6.17 mmol). The mixture was further sparged under nitrogen for 3 minutes and then heated to 80 °C for 16 hours. The mixture was cooled to room temperature, filtered through a bed of silica gel and CELITE and the bed was washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue purified by silica gel column chromatography (10 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 312.2 for [M + H]⁺.

Step 8: Preparation of methyl 4-amino-2,3-dihydro-1H-indene-5-carboxylate

Pd/C (10 wt%, 0.500 g, 0.470 mmol) was added to a solution of methyl 4-((4- methoxybenzyl)amino)-2,3-dihydro-1H-indene-5-carboxylate (1.00 g, 3.21 mmol) in ethyl acetate (30 mL). The vessel was sparged under hydrogen (1 atm) and stirred stirred at room temperature for 6 hours. The mixture was sparged under nitrogen and filtered through a CELITE bed, which was washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (0– 20 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 192.4 for [M + H]⁺. Step 9: Preparation of methyl 4-amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylate

A solution of bromine (0.194 mL, 3.77 mmol) in a 1:1 mixture of CCl₄ (5 mL) and dioxane (5 mL) was added to a solution of methyl 4-amino-2,3-dihydro-1H-indene-5- carboxylate (0.600 g, 3.14 mmol) in a 1:1 mixture of CCl₄ (5 mL) and dioxane (5 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and slowly treated with aqueous saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] (⁸¹Br) of 272.2 for [M + H]⁺.

Step 10: Preparation of 4-amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylic acid

LiOH.H₂O (0.177 g, 7.40 mmol) was added to a stirred solution of methyl 4- amino-7-bromo-2,3-dihydro-1H-indene-5-carboxylate (0.400 g, 1.48 mmol) in a 2:1:4 mixture of MeOH (4.00 ml): water (2.00 mL): tetrahydrofuran (8 ml). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and the residue was diluted with water (30 mL) and acidfied to pH ~ 6 with 6N aqueous hydrochloric acid. The mixture was extracted with dichloromethane and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 100 % ethyl aceate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 254.2 for [M]⁺.

Step 11: Preparation of 4-amino-7-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-2,3-dihydro- 1H-indene-5-carboxamide BOP (0.389 g, 0.879 mmol) followed by (1S,2S)-2-aminocyclohexanol (0.101 g, 0.879 mmol) was added to a stirred solution of 4-amino-7-bromo-2,3-dihydro-1H-indene-5- carboxylic acid (0.150 g, 0.586 mmol) and triethylamine (0.408 mL, 2.93 mmol) in a 4:1 mixture of dichloromethane (8 mL) and N,N-dimethylformamide (2 mL) at 0 °C. The mixture was stirred at room temperature for 4 hours, treated with aqueous saturated sodium bicarbonate, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 50 % ethyl aceate in petroleum ether) to provide the title compound that gave a mass ion [ES+] (81Br) of 355.2 for [M + H]⁺.

Step 12: Preparation of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-3,7,8,9-tetrahydro-4H- cyclopenta[h]quinazolin-4-one

A solution of 4-amino-7-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-2,3-dihydro- 1H-indene-5-carboxamide (0.140 g, 0.396 mmol) in N,N-dimethylformamide dimethyl acetal (5.00 mL, 37.6 mmol) was heated to 120 °C for 16 hours. The mixture was cooled to ambient temperature, concentrated in vacuo, and the residue was treated with water, and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 70 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] (81Br) of 365.0 for [M + H]⁺.

Step 13: Preparation of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)- 3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

(2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 1.5 mL, 0.74 mmol) was added to a solution of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-3,7,8,9-tetrahydro-4H- cyclopenta[h]quinazolin-4-one (0.090 g, 0.25 mmol) in THF (2 mL) at 0 °C, followed by addition of bis(tri-tert-butylphosphine)palladium(0) (6.3 mg, 0.012 mmol). The mixture was warmed to room temperature and stirred for 6 hours. The mixture was then cooled to 0 °C, treated with water (10 mL), and diluted with dichloromethane. The resulting solid was filtered off through a bed of CELITE and the filtrate was extracted with dichloromethane. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10– 90 % ethyl acetate in petroleum ether) to provide the title compound. ¹H NMR (400MHz ,

CD₃OD): δ 8.29– 8.24 (m, 2H), 7.88 (s, 1H), 7.63 (dd, J = 8.2, 2.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.14– 4.12 (m, 3H), 3.22 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.25– 2.17 (m, 3H), 1.97– 1.83 (m, 4H), 1.50– 1.47 (m, 3H) ppm. LRMS C₂₃H₂₅ClN₃O₂: calc’d 410.2, obs 410.2

(M+H) ⁺. Utilizing the general procedures described above, the following compounds were prepared: , 3O₃ .1 2

3O₂ .2 4

, . – .

(m, 3H) ppm ₃O₂ .2 2

3O₂ .2 4 . , , .

1.49 (m, 6H) ppm

Example 8, Compound 35 8-chloro-3-((1S,2S)-2-hydroxycy ylpyridin-3-yl)methyl)quinazolin- 4( 35

Scheme

Step 1: Preparation of 6-bromo-8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)quinazolin-4(3H)- one

Utilizing the procedures described for Compound 1, substituting 5-bromo-3- chloro-2-hydroxybenzoic acid for 2-hydroxy-3,4-dimethylbenzoic acid, the title compound was obtained.

Step 2: Preparation of 8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one

Potassium acetate (165 mg, 1.68 mmol) and bis(pinacolato)diboron (213 mg, 0.839 mmol) were added to a solution of 6-bromo-8-chloro-3-((1S,2S)-2- hydroxycyclohexyl)quinazolin-4(3H)-one (200 mg, 0.559 mmol) in 1,2-dimethoxyethane (8 mL) under nitrogen at room temperature. The mixture was sparged under nitrogen for 5 minutes and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (45.7 mg, 0.056 mmol). The mixture was heated at 80° C for 2 hours, cooled to room temperature, and diluted with ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and the combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50 % ethyl acetate in petroleum ether) to provide the title compound.

Step 3: Preparation of 8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one

A mixture of 8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one (130 mg, 0.321 mmol), cesium carbonate (314 mg, 0.964 mmol) and 5-(bromomethyl)-2-methylpyridine hydrobromide (103 mg, 0.385 mmol) in THF (5.0 ml) was sparged under nitrogen for 5 minutes. The mixture was treated with [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (26.2 mg, 0.032 mmol), sparged under nitrogen (3 minutes) and then heated at 60 °C for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (25 mL) and water (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, 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 yield the title compound. ¹H NMR (400MHz, CD₃OD): δ 8.35 (d, J = 2.0 Hz, 2H), 8.02 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.0, 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.51– 4.49 (m, 1H), 4.13 (s, 2H), 4.07– 4.02 (m, 1H), 2.51 (s, 3H), 2.20– 2.10 (m, 1H), 1.97– 1.84 (m, 4H), 1.48– 1.46 (m, 3H) ppm. LRMS C₂₁H₂₃ClN₃O₂: calc’d 384.1, obs 384.2 (M+H) ⁺. Example 9, Compound 36 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-8-vinylquinazolin-4(3H)-

A solution of 8-chloro-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3- yl)methyl)quinazolin-4(3H)-one (Compound 35, 30 mg, 0.078 mmol), 2,4,6- trivinylcyclotriboroxane pyridine complex (28 mg, 0.12 mmol) and potassium fluoride (14 mg, 0.23 mmol) in dioxane (4 mL) was sparged under nitrogen (5 minutes), and then treated with bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 7.8 μmol). The mixture was heated at 100 °C for 16 hours, cooled to room temperature, diluted with aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, 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 yield the title compound.¹H NMR (400MHz, CD₃OD): δ 8.35 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.69– 7.61 (m, 2H), 7.26 (d, J = 7.9 Hz, 1H), 5.92 (d, J = 17.8 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H), 4.51– 4.49 (m, 1H), 4.15 (s, 2H), 4.12– 4.09 (m, 1H), 2.51 (s, 3H), 2.17– 2.16 (m, 1H), 1.97– 1.84 (m, 4H), 1.49– 1.47 (m, 3H). LRMS C₂₃H₂₆N₃O₂: calc’d 376.2, obs 376.4 (M+H) ⁺. Example 10, Compound 37 8-ethyl-3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)quinazolin-4(3H)-

S h

Pd / C (10 wt%, 25 mg, 0.235 mmol) was added to a solution of 3-((1S,2S)-2- hydroxycyclohexyl)-6-((6-methylpyridin-3-yl)methyl)-8-vinylquinazolin-4(3H)-one

(Compound 36, 100 mg, 0.266 mmol) in methanol (5 mL). The vessel was sparged under hydrogen (1 atm) and stirred at room temperature for 2 hours. The mixture was sparged under nitrogen, filtered through a pad of CELITE, and washed with 1:1 dichloromethane and methanol. The combined filtrates were 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 yield the title compound.¹H NMR (400MHz , CD₃OD): δ 8.67 (s, 1H), 8.39– 8.33 (m, 2H), 7.96 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 5.50 (s, 1H), 4.54 (br s, 1H), 4.33 (s, 2H), 4.09 (br s, 1H), 3.09– 3.03 (m, 2H), 2.77 (s, 3H), 2.20– 2.13 (m, 1H), 1.95– 1.85 (m, 4H), 1.58– 1.48 (m, 3H), 1.39– 1.22 (m, 3H). LRMS C₂₃H₂₈N₃O₂: calc’d 378.2, obs 378.2 (M+H) ⁺. Example 11, Compound 38 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1,2,3,7,8,9- hexahydro-4H-cyclopenta[h]quinazolin-4-one, Compound 38

Step 1: Preparation of 3-((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6-((6- chloropyridin-3-yl)methyl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

Triethylamine (0.051 mL, 0.37 mmol) was added to a stirred solution of 6-((6- chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-3,7,8,9-tetrahydro-4H- cyclopenta[h]quinazolin-4-one (Compound 30, 50 mg, 0.12 mmol) in dichloromethane (5 mL) at 0 °C, followed by the addition of tert-butyldimethylsilyl trifluoromethanesulfonate (64 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (0– 40 % ethyl acetate in petroleum ether) to provide the title compound.

Step 2: Preparation of 3-((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6-((6- chloropyridin-3-yl)methyl)-1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one

NaBH₄ (0.18 g, 4.8 mmol) was added portion wise to a stirred solution of 3- ((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6-((6-chloropyridin-3-yl)methyl)-3,7,8,9- tetrahydro-4H-cyclopenta[h]quinazolin-4-one (50 mg, 0.095 mmol) in 1:1 mixture of MeOH (5 mL) and THF (5 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred for 4 hours. The mixture was cooled to 0 qC, diluted with ice-cold water (10 mL), and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo to provide the title compound. Step 3: Preparation of 3-((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6-((6- chloropyridin-3-yl)methyl)-1-methyl-1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4- one

NaH (11 mg, 0.28 mmol) was added to a solution of 3-((1S,2S)-2-((tert- butyldimethylsilyl)oxy)cyclohexyl)-6-((6-chloropyridin-3-yl)methyl)-1,2,3,7,8,9-hexahydro-4H- cyclopenta[h]quinazolin-4-one (50 mg, 0.095 mmol) in DMF (2 mL) at 0 °C under nitrogen, followed by the addition of MeI (0.012 mL, 0.190 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0 qC, diluted with cold water, and extracted with ethyl acetate. The combined organic extracts were washed with cold water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (0 - 50 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion [ES+] of 540.4 for [M]⁺

.

Step 4: Preparation of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-1- methyl-1,2,3,7,8,9-hexahydro-4H-cyclopenta[h]quinazolin-4-one

TBAF (0.74 ml, 0.74 mmol) was added to a 0 qC solution of 3-((1S,2S)-2-((tert- butyldimethylsilyl)oxy)cyclohexyl)-6-((6-chloropyridin-3-yl)methyl)-1-methyl-1,2,3,7,8,9- hexahydro-4H-cyclopenta[h]quinazolin-4-one (0.040 g, 0.074 mmol) in THF (2 mL) under nitrogen atmosphere. The mixture was stirred for 16 hours at room temperature, treated with with ice water, and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, 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. ¹H NMR (400MHz, DMSO-d₆): δ 8.29 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.2, 2.4 Hz, 1H), 7.45– 7.41 (m, 2H), 4.58 (d, J = 5.4 Hz, 1H), 4.44 (s, 2H), 4.09– 4.02 (m, 1H), 3.94 (s, 2H), 3.55– 3.45 (m, 1H), 2.86– 2.76 (m, 4H), 2.71 (s, 3H), 2.05– 2.02 (m, 3H), 1.98– 1.90 (m, 1H), 1.67– 1.52 (m, 6H) ppm. LRMS C₂₄H₂₉ClN₃O₂: calc’d 426.2, obs 426.4 (M+H) ⁺. Example 12, Compound 39 3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3-yl)methyl)-9,10- dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione, Compound 39

Step 1: Preparation of 5-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one

NaH (2.65 g, 66.4 mmol) was added to a solution of 5-bromo-3,4- dihydroquinolin-2(1H)-one (5.00 g, 22.1 mmol) in DMF (40 mL) at 0 °C under nitrogen, followed by the addition of methyl iodide (2.07 mL, 33.2 mmol). The mixture was stirred for 1 hour, diluted with cold water, and extracted with ethyl acetate. The combined organic extracts were washed with cold water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chroatography (0 - 5 % ethyl acetate in petroleum ether) to provide the title compound.

Step 2: Preparation of 5-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one Potassium hydroxide (0.514 g, 9.16 mmol) was added to a flask charged with tris(dibenzylideneacetone)dipalladium(0) (0.085 g, 0.092 mmol) and 5-bromo-1-methyl-3,4- dihydroquinolin-2(1H)-one (1.00 g, 4.16 mmol) under nitrogen. The reagents were suspended in dioxane (10 mL), sparged under nitrogen, and treated with 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (0.120 g, 0.250 mmol) and water (10 mL). The mixture was heated at 100 °C for 2 hours, cooled to room temperature, and treated with 1 N HCl (10 mL). The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 65 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 178.4 for [M + H]⁺.

Step 3: Preparation of 6-bromo-5-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one

Diisopropylamine (4.02 μL, 0.028 mmol) was added to a solution of 5-hydroxy-1- methyl-3,4-dihydroquinolin-2(1H)-one (0.050 g, 0.28 mmol) in dichloromethane (5 mL) under nitrogen. A solution of N-bromosuccinimide (0.055 g, 0.31 mmol) in dichloromethane (5 mL) was added to the mixture and was stirred at room temperature for 1 hour. The mixture was cooled to 0 qC, diluted with cold aqueous 2N H₂SO₄, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, 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 yield the title compound; mass ion [ES+] (⁸¹Br)of 258.4 for [M + H]⁺.

Step 4: Preparation of methyl 5-hydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6- carboxylate

Sodium acetate (673 mg, 8.20 mmol) was added to a stirred solution of 6-bromo- 5-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (700 mg, 2.73 mmol) in methanol (20 mL) under nitrogen, and the mixture was treated with [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (400 mg, 0.547 mmol). The mixture was heated at 75 °C for 16 hours under the pressure of carbon monoxide (4kg / cm). The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water, extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 35 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 236.2 for [M + H]⁺. Step 5: Preparation of methyl 1-methyl-2-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4- tetrahydroquinoline-6-carboxylate

Triflic anhydride (0.575 mL, 3.40 mmol) was added to a stirred solution of methyl 5-hydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.400 g, 1.70 mmol) in pyridine (20 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred for 3 hours. The mixture was cooled to 0 qC, diluted with ice-cold water (25 mL) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with sodium sulfate, 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 368.2 for [M + H]⁺. Step 6: Preparation of methyl 5-((4-methoxybenzyl)amino)-1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-6-carboxylate

A mixture of methyl 1-methyl-2-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4- tetrahydroquinoline-6-carboxylate (400 mg, 1.09 mmol) and cesium carbonate (1.06 g, 3.27 mmol) in toluene (20 mL) was sparged under nitrogen and then treated with palladium(II) acetate (48.9 mg, 0.218 mmol), BINAP (271 mg, 0.436 mmol) and 4-methoxybenzylamine (299 mg, 2.178 mmol). The mixture was again sparged under nitrogen (3 minutes) and heated at 80 °C for 16 hours. The mixture was cooled to ambient temperature, filtered through a bed of CELITE, and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and 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 355.2 for [M + H]⁺. Step 7: Preparation of methyl 5-amino-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6- carboxylate

Pd / C (10 wt%, 200 mg, 0.188 mmol) was added to a solution of methyl 5-((4- methoxybenzyl)amino)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (350 mg, 0.988 mmol) in ethyl acetate (30 mL). The mixture was sparged under hydrogen and the mixture was stirred under an atomsphere of hydrogen (1 atm) for 6 hours at room temperature. The mixture was sparged under nitrogen, filtered through a bed of CELITE, and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 235.2 for [M + H]⁺. Step 8: Preparation of methyl 5-amino-8-bromo-1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-6-carboxylate

A solution of bromine (0.053 mL, 1.025 mmol) in carbon tetrachloride (5 mL) and dioxane (5 mL) was added to a solution of methyl 5-amino-1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-6-carboxylate (200 mg, 0.854 mmol) in a 1:1 mixture of carbon tetrachloride (5 mL) and dioxane (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and treated with aqueous saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 50 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] (⁸¹Br) of 315.2 for [M + H]⁺. Step 9: Preparation of 5-amino-8-bromo-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6- carboxylic acid

LiOH.H₂O (76 mg, 3.2 mmol) was added to a stirred solution of methyl 5-amino- 8-bromo-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.639 mmol) in a mixture of MeOH (4 mL): water (2 mL): THF (8 mL). The mixture was stirred at room temperature for 16 hours, concentrated in vacuo, and treated with water (30 mL). The solution was acidified to ~pH 6 with 6N aqueous HCl, and then extracted with dichloromethane. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 100 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] (⁸¹Br) of 301.0 for [M + H]⁺. Step 10: Preparation of 5-amino-8-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-2- oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide

BOP reagent (0.444 g, 1.003 mmol) was added to a stirred solution of 5-amino-8- bromo-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (0.200 g, 0.669 mmol) and triethylamine (0.466 mL, 3.34 mmol) in a 4:1 mixture of dichloromethane (8 mL): DMF (2 mL) at 0°C, followed by the addition of (1S,2S)-2-aminocyclohexanol (0.116 g, 1.003 mmol). The mixture was stirred at room temperature for 4 hours, treated with aqueous saturated sodium bicarbonate, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 50 % ethyl aceate in petroleum ether) to provide the title compound; mass ion [ES+] of 397.2 for [M + H]⁺. Step 11: Preparation of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-9,10- dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione

A solution of 5-amino-8-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-2- oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide (0.170 g, 0.429 mmol) in N,N- dimethylformamide dimethyl acetal (5.00 ml, 37.6 mmol) was heated to 120 °C for 16 hours. The mixture was concentrated in vacuo and the residue was treated with water, and extracted with ethyl acetate. The combined organic extract was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0– 70 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] (⁸¹Br) of 408.2 for [M + H]⁺.

Step 12: Preparation of 6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)- 7-methyl-9,10-dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione

(2-chloro-5-pyridyl)methylzinc chloride solution (0.5 M in THF, 1.3 mL, 0.66 mmol) was added to a solution of 6-bromo-3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-9,10- dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione (0.090 g, 0.22 mmol) in THF (2 mL) at 0 °C, followed by the addition of Bs(tri-tert-butylphosphine)palladium(0) (5.6 mg, 0.011 mmol). The mixture was warmed to room temperature, stirred 6 hours, and then cooled to 0 °C. The mixture was treated with water (10 mL), diluted with dichloromethane/water, and the resulting solid was filtered off through a bed of CELITE. The filtrate was extracted with dichloromethane and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10– 90 % ethyl acetate in petroleum ether) to provide the title compound; mass ion [ES+] of 453.2 for [M + H]⁺.

Step 13: Preparation of 3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-6-((6-methylpyridin-3- yl)methyl)-9,10-dihydropyrido[2,3-h]quinazoline-4,8(3H,7H)-dione

Tetramethyltin (0.16 g, 0.88 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.044 mmol) was added to a stirred solution of 6-((6-chloropyridin-3- yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)-7-methyl-9,10-dihydropyrido[2,3-h]quinazoline- 4,8(3H,7H)-dione (40 mg, 0.088 mmol) in DMF (5 mL) under nitrogen at room temperature. The mixture was heated at 90 ^oC for 16 hours, cooled to room temperature, and diluted with cold water. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with cold water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 5 % methanol in

dichloromethane) to provide the title compound. ¹H NMR (400MHz , DMSO-d₆): δ 8.41 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.34 (dd, J = 8.0, 2.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.89 (d, J = 5.6 Hz, 1H), 4.20 (s, 2H), 3.98– 3.85 (m, 1H), 3.26 (s, 3H), 3.23– 3.19 (m, 2H), 2.43 (s, 3H), 2.03– 1.91 (m, 1H), 1.77– 1.62 (m, 4H), 1.31– 1.24 (m, 3H) ppm. LRMS C₂₅H₂₉N₄O₃: calc’d 433.2, obs 433.2 (M+H) ⁺. EXAMPLE 13, Compound 40 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H- [1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one, Compound 40

Step 1: Preparation of N1-methyl-5-nitrobenzene-1,2-diamine

Iodomethane (7.41 g, 52.2 mmol) and aqueous saturated sodium carbonate (16 mL) were added to a solution of 4-nitrobenzene-1,2-diamine (10.0 g, 65.3 mmol) in DMF (60 mL). The mixture was stirred at room temperature for 48 hours, concentrated in vacuo, and extracted with water (200 mL). The mixture was extracted with ethyl acetate (2 x 300 mL) and the combined organic extracts were washed with 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 166.2 [M- H]⁺.

Step-2 Synthesis of 1-methyl-6-nitro-1H-benzo[d][1,2,3]triazole

An aqueous solution of sodium nitrite (2.64 g, 38.3 mmol) was added slowly to a solution of N1-methyl-5-nitrobenzene-1,2-diamine (3.2 g, 19.14 mmol) in aqueous 5M HCl (70 mL) at -5 °C. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was basified with saturated aqueous ammonium hydroxide to a pH 8. The mixture was extracted with ethyl acetate (100 mL) and the organic extract was washed with water (3 x 100ml). The combined organic extract was washed with 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.

Step 3: Preparation of 1-methyl-1H-benzo[d][1,2,3]triazol-6-amine

Palladium on carbon (0.300 g, 0.282 mmol) was added to a solution of 1-methyl- 6-nitro-1H-benzo[d][1,2,3]triazole (3.00 g, 16.8 mmol) in EtOH (60 mL). The mixture was sparged under an atmosphere of hydrogen (1 atm) and stirred for 24 hours. The mixture was sparged under nitrogen, filtered through a pad of CELITE, and the solids were washed with EtOH. The filtrate was concentrated in vacuo to provide the title compound; mass ion (ES+) of 149.4 [M+H]⁺.

Step 4: Preparation of N-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)

Acetic anhydride (2.60 g, 25.5 mmol) was added to a solution of 1-methyl-1H- benzo[d][1,2,3]triazol-6-amine (1.80 g, 12.1 mmol) in dioxane (20 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, treated with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with Na₂SO₄, fitlered, and concentrated in vacuo to provide the title compound; mass ion (ES+) of 191.2 [M+H]⁺.

Step 5: Preparation of N-(1-methyl-7-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acetamide Concentrated aqueous nitric acid (12 mL) was added slowly to a solution of 12N aqueous sulfuric acid (12 mL) and N-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)acetamide (2.00 g, 10.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 hours, treated with ice, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound.

Step 6: Preparation of 1-methyl-7-nitro-1H-benzo[d][1,2,3]triazol-6-amine

Borontrifluoride diethyletherate (4.07 g, 28.7 mmol) was added to a solution of N- (1-methyl-7-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acetamide (1.50 g, 6.38 mmol) in MeOH (10 mL) at room temperature. The mixture was heated at 70 °C for 3 hours, cooled to ambient temperature, treated with aqueous saturated sodium bicarbonate, and concentrated in vacuo. The residue was treated with water and extracted with dichloromethane. The combined organic extracts were washed with brine, dried with Na₂SO₄, fitlered, and concentrated in vacuo to provide the title compound.

Step 7: Preparation of 6-bromo-1-methyl-7-nitro-1H-benzo[d][1,2,3]triazole

Copper(II) bromide (1.25 g, 5.59 mmol) was added to a solution of 1-methyl-7- nitro-1H-benzo[d][1,2,3]triazol-6-amine (900 mg, 4.66 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 15 minutes and the treated with tert-butyl nitrite (577 mg, 5.59 mmol). The mixture was heated at 60 °C for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 30% dichloromethane in hexane, filtered through a pad of CELITE, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0- 8 % ethyl acetate in petroleum ether) to provide the title compound.

Step 8: Preparation of methyl 1-methyl-7-nitro-1H-benzo[d][1,2,3]triazole-6-carboxylate

A mixture of 6-bromo-1-methyl-7-nitro-1H-benzo[d][1,2,3]triazole (650 mg, 2.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (83 mg, 0.10 mmol), and triethylamine (0.176 mL, 1.26 mmol) in MeOH (10 mL) was sparged under 100 psi of carbon monoxide. The mixture was heated at 60 °C for 24 hours, cooled to ambient temperature, filtered through a pad of CELITE and concentrated in vacuo. The residue was dissolved in 20 mL of ethyl acetate, washed with water and brine, dried with sodium sulfate, filtered, and 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 9: Preparation of methyl 7-amino-1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate Palladium on carbon (65 mg, 0.061 mmol) was added to a solution of methyl 1- methyl-7-nitro-1H-benzo[d][1,2,3]triazole-6-carboxylate (650 mg, 2.75 mmol) in EtOH (5 mL) and THF (20 mL). The mixture was sparged under an atmosphere of hydrogen (1 atm) and stirred at ambient temperature for 6 hours. The mixture was sparged under nitrogen, filtered through a pad of CELITE, and the solids were washed with EtOH. The combined fiiltrates were concentrated in vacuo to provide the title compound.

Step 10: Preparation of methyl 7-amino-4-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-6- carboxylate

A^{solution of bromine (0.128 mL, 2.48 mmol) in a mixture of 1:1 dioxane: CCl} ₄ (6 mL) was added drop-wise to a stirred solution of methyl 7-amino-1-methyl-1H- benzo[d][1,2,3]triazole-6-carboxylate (350 mg, 1.69 mmol) in a mixture of 1:1 dioxane : CCl₄ (5 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours, and the solid was filtered off and washed with hexane. The solid was dried in vacuo to provide the title compound.

Step 11: Preparation of 7-amino-4-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylic acid

Lithium hydroxide (134 mg, 5.61 mmol) was added to a stirred solution of methyl 7-amino-4-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (320 mg, 1.12 mmol) in MeOH (5 mL), tetrahydrofuran (5 mL) and water (2 mL) at 0 °C. After stirring at 0 °C for 5 minutes, the mixture was stirred at room temperature for 16 hours. The mixture was

concentrated in vacuo and acidified with aqueous hydrochloric acid to a pH ~3. The solid was collected via filtration, washed twice with water, and dried in vacuo to provide the title compound; mass ion (ES+) of 271.2 [M]⁺.

Step 12: Preparation of 7-amino-4-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H- benzo[d][1,2,3]triazole-6-carboxamide

BOP (661 mg, 1.49 mmol), (1S,2S)-2-aminocyclohexanol (115 mg, 0.996 mmol) and TEA (0.416 mL, 2.99 mmol) was added to a stirred solution of 7-amino-4-bromo-1-methyl- 1H-benzo[d][1,2,3]triazole-6-carboxylic acid (270 mg, 0.996 mmol) in DMF (5 ml) at room temperature. The mixture was stirred for 16 hours at room temperature, treated with cold water, and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried with Na₂SO_4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 40 % ethyl acetate in petroleum ether) to provide the title compound; mass ion (ES+) of 368.2 [M]⁺. Step 13: Preparation of 4-bromo-7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H- [1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one

A solution of 7-amino-4-bromo-N-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H- benzo[d] [1,2,3]triazole-6-carboxamide (200 mg, 0.543 mmol) in N,N-dimethyl formamide dimethyl acetal (64.7 mg, 0.543 mmol) was heated at 140 °C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 20 % ethyl acetate in petroleum ether) to provide the title compound; mass ion (ES+) of 378.2 [M]⁺.

Step 14: Preparation of 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)- 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one

A solution of (2-chloro-5-pyridyl)methylzinc chloride (180 mg, 0.793 mmol) was added to a solution of 4-bromo-7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H- [1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one (100 mg, 0.264 mmol) in tetrahydrofuran (3 mL) at 0 °C, followed by the addition of bis(tri-tert-butylphosphino)palladium (0) (6.8 mg, 0.013 mmol). The mixture was warmed to ambient temperature and stirred for 3 hours. The mixture was cooled to 0 °C and treated with water (5 mL). The mixture was diluted with DCM/water and the resulting solid was filtered off through a bed of CELITE. The filtrate was extracted with dichloromethane (2x10 mL) and the combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 80 % ethyl acetate in petroleum ether) to provide the title compound.¹H NMR (400MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.54-8.51 (m, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 4.98 (d, J = 5.0 Hz, 1H), 4.67 (s, 3H), 4.54 (s, 2H), 4.04-4.01 (m, 1H), 2.02-1.98 (m, 1H), 1.88-1.86 (m, 1H), 1.76-1.72 (m, 2H), 1.38-1.35 (m, 3H) ppm. LRMS C₂₁H₂₂ClN₆O₂: calc’d 425.1, obs 424.9 (M+H) ⁺. EXAMPLE 14, Compound 41 7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-4-((6-methylpyridin-3-yl)methyl)-1,7-dihydro- 6H-[1,2,3]triazolo[4,5-h]quinazolin-6-one, Compound 41

Bis(triphenylphosphine)palladium(II)dichloride (3.3 mg, 4.7 μmol) and tetramethyltin (25 mg, 0.14 mmol) was added to a solution of 4-((6-chloropyridin-3-yl)methyl)- 7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazolin-6(7H)-one (Compound 40, 40 mg, 0.094 mmol) in DMF (2 mL) under an atmosphere of nitrogen at room temperature. 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 (50– 60 % ethyl acetate in petroleum ether) to provide the title compound. ¹H NMR (400MHz, DMSO-d₆): δ 8.54 (s, 1H), 8.48 (s, 1H), 7.93 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.76 (s, 3H), 4.63 (s, 1H), 4.56 (s, 2H), 3.37 (s, 2H), 2.50 (s, 3H), 2.22-2.17 (m, 1H), 2.05-1.98 (m, 1H), 1.83-1.92 (m, 2H), 1.65-1.50 (m, 3H) ppm. LRMS C₂₂H₂₅N₆O₂: calc’d 405.2, obs 405.4 (M+H) ⁺. Example 15, Compound 42 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)-1-methyl-1,7-dihydro- 6H-imidazo[4,5-h]quinazolin-6-one, Compound 42

Step 1: Preparation of N1-methyl-5-nitrobenzene-1,2-diamine

Iodomethane (7.41 g, 52.2 mmol) and saturated aqueous sodium carbonate (16 mL) was added to a solution of 4-nitrobenzene-1,2-diamine (10.0 g, 65.3 mmol) in DMF (60 mL). The mixture was stirred at room temperature for 48 hours, concentrated in vacuo, and treated with water (300 mL). The mixture was extracted with ethyl acetate (2 x 300 mL) and the combined organic extracts were washed with 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 166.2 [M-H]⁺.

Step 2: Preparation of 1-methyl-6-nitro-1H-benzo[d]imidazole

A mixture of N1-methyl-5-nitrobenzene-1,2-diamine (1.30 g, 7.78 mmol) and formic acid (10.0 mL, 261 mmol) was stirred at room temperature for 30 minutes and then refluxed for 4 hours. The mixture was cooled to ambient temperature, concentrated in vacuo, and the residue was triturated with dilute aqueous ammonium hydroxide. The resultant solid was filtered, washed with water, and dried in vacuo to provide the title compound; mass ion (ES+) of 178.2 [M-H]⁺.

Step-3:1-methyl-1H-benzo[d]imidazol-6-amine

Palladium on carbon (0.300 g, 2.82 mmol) was added to a solution of 1-methyl-6- nitro-1H-benzo[d]imidazole (1.00 g, 5.64 mmol) in methanol (10 mL). The mixture was sparged under an atmosphere of of hydrogen (1 atm) and stirred at ambient temperature for 16 hours. The mixture was sparged under nitrogen, filtered through a CELITE pad, and the solids were washed with methanol. The combined filtrates were concentrated in vacuo to provide the title compound.

Step 4: Preparation of N-(1-methyl-1H-benzo[d]imidazol-6-yl)acetamide

Acetic anhydride (1.08 ml, 11.4 mmol) was added to a solution of 1-methyl-1H- benzo[d]imidazol-6-amine (800 mg, 5.44 mmol) in dioxane (20 mL) at 0 °C. The mixture was stirred at room temperature for 16 hours, concentrated in vacuo, and the residue was diluted with water. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound; mass ion (ES+) of 190.4 [M+H]⁺.

Step 5: Preparation of N-(1-methyl-7-nitro-1H-benzo[d]imidazol-6-yl)acetamide

Concentrated nitric acid (5.0 mL, 78 mmol) was added slowly to a solution of concentrated sulfuric acid (0.237 mL, 4.44 mmol) and N-(1-methyl-1H-benzo[d]imidazol-6- yl)acetamide (700 mg, 3.70 mmol) at 0 °C. The mixture was stirred at 0 qC for 4 hours, treated with ice, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to provide a mixture of N-(1- methyl-7-nitro-1H-benzo[d][1,2,3]triazol-6-yl)acetamide and N-(1-methyl-5-nitro-1H- benzo[d]imidazol-6-yl)acetamide. The title compound was obtained by preparative reverse phase HPLC (90:10 to 0:100; water containing 0.1% formic acid : acetonitrile containing 0.1% formic acid).

Step 6: Preparation of 1-methyl-7-nitro-1H-benzo[d]imidazol-6-amine

Borontrifluoride diethyletherate (1.89 ml, 14.9 mmol) was added to a solution of N-(1-methyl-7-nitro-1H-benzo[d]imidazol-6-yl)acetamide (700 mg, 2.99 mmol) in methanol (10 mL) at room temperature. The mixture was heated at 70 °C for 3 hours, cooled to ambient temperature, and treated with aqueous saturated sodium bicarbonate. The mixture was concentrated in vacuo, and the residue was diluted with water and extracted with

dichloromethane. The combined organic extracts were washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound that gave a mass ion (ES+) of 193.2 [M]⁺.

Step 7: Preparation of 6-bromo-1-methyl-7-nitro-1H-benzo[d]imidazole

Copper (II) bromide (837 mg, 3.75 mmol) was added to a solution of 1-methyl-7- nitro-1H-benzo[d]imidazol-6-amine (600 mg, 3.12 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 15 minutes and then treated with tert-butyl nitrite (386 mg, 3.75 mmol). The mixture was heated at 60 °C for 3 hours, cooled to ambient temperature, and concentrated in vacuo. The residue was dissolved in 30% dichloromethane in hexane, and filtered through a bed of CELITE. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (0 - 80 % ethyl acetate in petroleum ether) to provide the title compound.

Step 8: Preparation of 1-methyl-7-nitro-1H-benzo[d]imidazole-6-carbonitrile

Copper(I) cyanide (262 mg, 2.93 mmol) was added to a flask charged with 6- bromo-1-methyl-7-nitro-1H-benzo[d]imidazole (500 mg, 1.95 mmol) in anhydrous DMF (5 mL). The mixture was heated at 120 °C for 12 hours, cooled to ambient temperature, poured into ice, ^{and extracted with dichloromethane (3 x 80 mL). The organic extracts were dried with Na} ₂ ^SO ₄ ^, filtered, and concentrated in vacuo. The residue was purified by silica gel column

chromatography (0– 75 % ethyl acetate in petroleum ether) to provide the title compound.

Step 9: Preparation of 1-methyl-7-nitro-1H-benzo[d]imidazole-6-carboxylic acid

A solution of 1-methyl-7-nitro-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 2.47 mmol) in 48% aqueous hydrobromic acid (280 μL, 2.47 mmol) was heated to 100 °C for 12 hours, cooled to room temperature, and concentrated with toluene in vacuo to provide the title compound.

Step 10: Preparation of methyl 1-methyl-7-nitro-1H-benzo[d]imidazole-6-carboxylate

Thionyl chloride (0.223 mL, 3.05 mmol) was added dropwise to a cooled 0° C solution of 1-methyl-7-nitro-1H-benzo[d]imidazole-6-carboxylic acid (450 mg, 2.03 mmol) in methanol (10 mL). The mixture was stirred for 15 minutes at 0 qC, warmed to room

temperature, and then heated to 65 °C for 6 hours. The mixture was concentrated in vacuo, ^{treated with aqueous saturated NaHCO} ₃ ^{(15 mL) and extracted with dichloromethane (2 x} ^{20mL). The organic extracts were dried with Na} ₂ ^SO ₄ ^{, filtered, and concentrated in vacuo. The} residue was purified by silica gel column chromatography (0– 65 % ethyl acetate in petroleum ether) to provide the title compound.

Step 11: Preparation of methyl 7-amino-1-methyl-1H-benzo[d]imidazole-6-carboxylate Palladium on carbon (181 mg, 1.70 mmol) was added to a solution of methyl 1- methyl-7-nitro-1H-benzo[d]imidazole-6-carboxylate (400 mg, 1.70 mmol) in methanol (8 mL). The mixture was sparged under an atmosphere of hydrogen (1 atm) and stirred at ambient temperature for 6 hours. The reaction mixture was sparged under nitrogen, filtered through a pad of CELITE, and the solids were washed with MeOH. The combined filtrates were concentrated in vacuo, to provide the title compound.

Step 12: Preparation of methyl 7-amino-4-bromo-1-methyl-1H-benzo[d]imidazole-6- carboxylate

Methyl 7-amino-1-methyl-1H-benzo[d]imidazole-6-carboxylate (400 mg, 1.70 mmol ) was dissolved in a 1:1 mixture of 1,4-dioxane (8 mL): CCl₄ (8 mL), cooled to 0 °C, and treated with a CCl₄ (4 mL) solution of bromine (272 mg, 1.701 mmol) dropwise. The mixture was stirred at 0 °C for 2 hours and the resulting solid was filtered, washed with hexane, and dried in vacuo to provide the title compound.

Step 13: Preparation of of methyl 7-amino-4-((6-chloropyridin-3-yl)methyl)-1-methyl-1H- benzo[d]imidazole-6-carboxylate

A solution of bis(tri-tert-butylphosphino)palladium(0) (90 mg, 0.18 mmol) was added to a solution of methyl 7-amino-4-bromo-1-methyl-1H-benzo[d]imidazole-6-carboxylate (200 mg, 0.704 mmol) in tetrahydrofuran (5 mL) at 0 °C, followed by the addition of (4- chlorobenzyl)zinc(II) chloride (478 mg, 2.112 mmol). The mixture was warmed to room temperature and stirred for 16 hours. The mixture was cooled to 0 °C, treated with water (5 mL), and diluted with dichloromethane and water. The resulting precipitate was removed via filtration through a bed of CELITE. The filtrate was extracted with dichloromethane (2x10 mL) and the combined organic extracts were dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 80 % ethyl acetate in petroleum ether) to provide the title compound that gave a mass ion (ES+) of 331.4 [M+H]⁺.

Step 14: Preparation of 7-amino-4-((6-chloropyridin-3-yl)methyl)-1-methyl-1H-benzo[d] imidazole-6-carboxylic acid

Lithium hydroxide (43.4 mg, 1.81 mmol) was added to a stirred solution of methyl 7-amino-4-((6-chloropyridin-3-yl)methyl)-1-methyl-1H-benzo[d]imidazole-6- carboxylate (150 mg, 0.453 mmol) in MeOH (2 mL), tetrahydrofuran (2 mL) and water (1 mL) at 0 °C. After stirring at 0 °C for 5 minutes, the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and the residue was treated with hydrochloric acid until a pH 3. The resulting solid was collected via filtration, washed twice with water and dried in vacuo to provide the title compound that gave a mass ion (ES+) of 317.4 [M]⁺.

Step 15: Preparation of 7-amino-4-((6-chloropyridin-3-yl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl )-1-methyl-1H-benzo[d]imidazole-6-carboxamide

BOP (251 mg, 0.568 mmol), (1S,2S)-2-aminocyclohexanol (43.6 mg, 0.379 mmol) and TEA (0.132 mL, 0.947 mmol) were added to a stirred solution of 7-amino-4-((6- chloropyridin-3-yl)methyl)-1-methyl-1H-benzo [d]imidazole-6-carboxylic acid (120 mg, 0.379 mmol) in DMF (3 mL) at room temperature. The mixture was stirred for 12 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 to provide the title compound.

Step 16: Preparation of 4-((6-chloropyridin-3-yl)methyl)-7-((1S,2S)-2-hydroxycyclohexyl)- 1-methyl-1,7-dihydro-6H-imidazo[4,5-h]quinazolin-6-one

N,N-dimethyl formamide dimethyl acetal (0.097 mL, 0.72 mmol) was added to a solution of 7-amino-4-((6-chloropyridin-3-yl)methyl)-N-((1S,2R)-2-hydroxycyclohexyl)-1- methyl-1H-benzo[d]imidazole-6-carboxamide (60 mg, 0.14 mmol) in DMF (1 mL). The mixture was heated at 120 °C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. 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. ¹H NMR (400MHz, CD₃OD): δ 8.40 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.78 (dd, J = 8.0, 4.0 Hz, 1H), 7.36 (s, 1H), 4.48 (s, 2H), 4.39 (s, 3H), 4.06-4.02 (m, 1H), 2.15- 2.08 (m, 1H), 2.01 -1.96 (m, 1H), 1.94-1.87 (m, 2H), 1.52-1.50 (m, 3H) ppm. LRMS

C₂₂H₂₅N₆O₂: calc’d 424.2, obs 424.2 (M+H) ⁺. Example 16

M1 Receptor Positive Allosteric Modulator Activity

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, are added. For M2Gqi5CHO-NFAT and M4Gqi5CHO-NFAT cells, an additional 600 ug/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 were 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 was 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. This 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. This 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 3 nM 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) added as a control. Using Temo, 49 μl assay buffer is added to each well of the 384-well plate right before assay.

In a 96-well Whatman 2ml Uniplate, 9 nM Acetylcholine (3x) was 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.

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. WO2004/073639.

In particular, the compounds of the examples had activity in the aforementioned assay, generally with an IP (inflection point) of 10 μM (10,000 nM) or less. The inflection point was 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 in the Table below: Table. FLIPR Assay Data: Different laboratory values are noted where present.

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.

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

(a) hydrogen,

(b) a 6-membered aryl,

(d) halogen,

(e)–CN,

(^f)–O-C ₁ ^-C ₆ ^alkyl,

(^g)–C ₁ ^-C ₆ ^alkyl, ^(h)–C ₂ ^-C ₆ ^alkenyl,

(i)–S(=O)_k–R²,

(j)–(C(O)O)_mN(R^3A)(R^3B),

(k)–OH, and

(l) -C(=O)-(O)_m–R⁴,

(a) hydrogen,

(b)–C_1-C₆ alkyl,

(c)–C_3-C₆ cycloalkyl,

(d)–C(=O)-R⁴,

(e)–C(=O)-O-R⁴, and

(f)–S(O)₂-R⁴,

or, alternatively, R^3A and R^3B, together with the attached nitrogen, form a 3-6 membered nitrogen-containing heterocyclic ring optionally having one to three additional heteroatoms selected from N, O and S; each occurrence of R^6Aand R^6B is independently selected from hydrogen, fluorine,–O-C₁-C₆ ^{alkyl, and -C} ₁ ^-C ₆ ^{alkyl, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said -C} ₁ ^-C ₆ ^{alkyl, are optionally} substituted with one to four substitutents independently selected from fluorine,–C₁-C₆ alkyl, and ^–OC ₁ ^-C ₆ ^alkyl; each occurrence of R⁷ is independently hydrogen or halogen; ^{R8 and R9 are independently hydrogen, halogen, hydroxy,–O-C} ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^alkyl,–C ₂ ^-C ₆ alkenyl,–C(=O)-(O)_m–R⁴,–N(R^3A)(R^3B), or–S(=O)_k–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said–C} ₁- ^C ₆ ^{alkyl, and said–C} ₂ ^-C ₆ ^{alkenyl are optionally substituted with one to three substitutents} ^{independently selected from halogen and C} ₁ ^-C ₆ ^alkyl; or, alternatively, R⁸ and R⁹, together with their attached carbon atoms, form a 5-6 membered ring fused to the benzene to which R⁸ and R⁹ are attached wherein said 5-6 membered ring is selected from the group consisting of:

(a) a 5-6 membered cycloalkyl ring,

(b) a 5-6 membered heterocycloalkyl ring having one to three heteroatoms

selected from N, O and S, and

and wherein said 5-6 membered cycloalkyl ring, said 5-6 membered heterocycloalkyl ring or said 5-membered heteroaryl ring is optionally substituted with one to three substituents ^{independently selected from halogen, oxo, 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–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said–C} ₁ ^-C ₆ ^alkyl are optionally substituted with one to three substitutents independently selected from halogen ^{and C} ₁ ^-C ₆ ^alkyl; ^{R10 is hydrogen, halogen, hydroxy,–O-C} ₁ ^-C ₆ ^{alkyl, -C} ₁ ^-C ₆ ^{alkyl,–S(=O)} _k ^-R2,–C₂-C₆ alkenyl,– ^{CN, -C(=O)-(O)} _m ^{-R4,–N(R3A)(R3B), -C} ₆ ^-C ₁₀ ^{aryl, -C} ₅ ^-C ₁₀ ^{heteroaryl, -C} ₅ ^-C ₁₀ ^{heterocycloalkyl,} ^{or -OC(=O)- R4, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, said -C} ₁ ^-C ₆ ^{alkyl, said–C} ₂ ^-C ₆ ^{alkenyl, said -C} ₆- ^C ₁₀ ^{aryl, said -C} ₅ ^-C ₁₀ ^{heteroaryl and said -C} ₅ ^-C ₁₀ ^{heterocycloalkyl are optionally substituted with} one to four substitutents independently selected from halogen,–C₁-C₆ alkyl, and–OC₁-C₆ alkyl; R¹¹ when present is selected from the group consisting of:

(a) hydrogen,

(b) halogen, and

(c)–C_1-10 alkyl, optionally substituted with one to three substituents independently selected from oxo and–OH; k is 0, 1 or 2; n is 0, 1 or 2;

m is 0 or 1;

(i) when p is 1, the dashed bond represents a single bond; and

ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH_3;

i. hydrogen and–CH₃;

ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH₃; and

i. hydrogen and–CH₃;

ii. –CH₃ and hydrogen;

iii. hydrogen and hydrogen; or

iv. –CH₃ and–CH₃. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each occurrence of X is CH₂.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one occurrence of X is O and the remaining occurrences of X are CH₂. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one occurrence of X is NH and the remaining occurrences of X are CH₂. 5. A compound according to any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein one occurrence of Z is CH and the other is N. 6. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹ are independently hydrogen, halogen, hydroxy,–O- ^C ₁ ^-C ₆ ^alkyl,–C ₁ ^-C ₆ ^{alkyl, or–C} ₂ ^-C ₆ ^alkenyl; 7. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt thereof wherein R⁸ and R⁹, together with their attached carbon atoms, form a 5-6 membered ring fused to the benzene to which R⁸ and R⁹ are attached wherein said 5-6 membered ring is selected from the group consisting of:

(a) a 5-6 membered cycloalkyl ring,

(b) a 5-6 membered heterocycloalkyl ring having one to three heteroatoms

selected from N, O and S, and

N(R^3A)(R^3B), and–S(=O)_k–R^{5, wherein said–O-C} ₁ ^-C ₆ ^{alkyl, and said–C} ₁ ^-C ₆ ^{alkyl are optionally} substituted with one to three substitutents independently selected from halogen and C₁-C₆ alkyl. 8. A compound according to claims 1-7, or a pharmaceutically acceptable salt thereof, wherein p is 0, the dashed bond represents a double bond, and R¹¹ is absent.

9. A compound according to claims 1-7, or a pharmaceutically acceptable salt thereof, wherein p is 1, the dashed bond represents a single bond, and R¹¹ is selected from the group consisting of:

(a) hydrogen,

(b) halogen, and

(c)–C_1-10 alkyl, optionally substituted with one to three substituents

independently selected from oxo and–OH.

,

, , or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. 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 sleep disorders, comprising a therapeutically effective amount of a compound of any of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. Use of a pharmaceutical composition of any of claims 1-10 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.

14. Use of a compound of any of claims 1-10, 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. 15. 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, comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1- 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.